Gamma-diketones as wnt/beta -catenin signaling pathway activators

ABSTRACT

The present disclosure provides γ-diketones or analogs thereof, that activate Wnt/β-catenin signaling and thus treat or prevent diseases related to signal transduction, such as osteoporosis and osteoarthropathy; osteogenesis imperfecta, bone defects, bone fractures, periodontal disease, otosclerosis, wound healing, craniofacial defects, oncolytic bone disease, traumatic brain injuries or spine injuries, brain atrophy/neurological disorders related to the differentiation and development of the central nervous system, including Parkinson&#39;s disease, strokes, ischemic cerebral disease, epilepsy, Alzheimer&#39;s disease, depression, bipolar disorder, schizophrenia; otic disorders like cochlear hair cell loss; eye diseases such as age related macular degeneration, diabetic macular edema or retinitis pigmentosa and diseases related to differentiation and growth of stem cell, such as hair loss, hematopoiesis related diseases and tissue regeneration related diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.No. 61/768,033, filed Feb. 22, 2013, which is incorporated by referencein its entirety herein.

BACKGROUND

1. Technical Field

This disclosure relates to activators of one or more proteins in the Wntpathway, including activators of one or more Wnt proteins, andcompositions comprising the same. More particularly, it concerns the useof a γ-diketones or salts or analogs thereof, in the treatment ofosteoporosis and osteoarthropathy; osteogenesis imperfecta; bonedefects; bone fractures; periodontal disease; otosclerosis; woundhealing; craniofacial defects; oncolytic bone disease; traumatic brainor spine injuries; brain atrophy/neurological disorders related to thedifferentiation and development of the central nervous system, includingParkinson's disease, strokes, ischemic cerebral disease, epilepsy,Alzheimer's disease, depression, bipolar disorder, and schizophrenia;otic disorders like cochlear hair cell loss; eye diseases such as agerelated macular degeneration, diabetic macular edema or retinitispigmentosa; and diseases related to differentiation and growth of stemcell, such as hair loss, hematopoiesis related diseases and tissueregeneration related diseases.

2. Background

The Wnt/β-catenin signaling pathway is involved in many biologicalprocesses. For example, aberrant activation of the Wnt/β-catenin pathwayhas led to several phenotypes, including the development of a variety ofhuman cancers, and diseases leading to abnormal development andfunctioning of stem cells [Oncogene (2009), 28(21), 2163-2172; CancerCell (2008), 14(6), 471-484; American Journal of Pathology (2003),162(5), 1495-1502]. Chronic activation of the Wnt/β-catenin signalingpathway has been implicated in the development of a variety of humanmalignancies, including high bone mass syndrome, sclerosteosis,colorectal carcinomas, hepatocellular carcinomas (HCCs), ovarian,uterine, pancreatic carcinomas, and melanomas [BioEssays (1999) 21(12),1021-1030; Cell (2000), 103(2), 311-320; Genes Dev. (2000), 14(15),1837-1851]. Since the Wnt/β-catenin pathway is involved in a number ofgrowth and development processes, mutation of the proteins involved inthe Wnt/β-catenin signal transduction system has also been linked toother human diseases such as abnormalities in development, hair folliclemorphogenesis, stem cell differentiation, bone formation, and cellproliferation.

SUMMARY

The present disclosure relates to methods for increasing cell or tissueregeneration in a vertebrate patient. The disclosure relates to methodsfor increasing the activity of embryonic and/or adult stem cells,progenitor cells, mesenchymal progenitor/stem cells and/ordifferentiated cells in vivo in a vertebrate patient. The disclosurefurther relates to methods for increasing cell or tissue regeneration ina vertebrate patient by administering to a vertebrate patient in needthereof a compound according to Formula I, II, III, IIIa, IIIb, and/orIV, and increasing a stem cell, progenitor cell, and/or differentiatedcell population in the vertebrate patient as compared to the stem cell,progenitor cell, and/or differentiated cell population in the vertebratepatient before treatment. Increasing the stem cell, progenitor cell, ordifferentiated cell population in the vertebrate patient can be a resultof one or more of cell proliferation, cell horning, decreased apoptosis,self-renewal, and increased cell survival.

In one embodiment, the cell or tissue regeneration can occur in tissuesincluding but not limited to, bone, chondrocytes/cartilage, muscle,skeletal muscle, cardiac muscle, pancreatic cells, endothelial cells,vascular endothelial cells, adipose cells, liver, skin, connectivetissue, hematopoietic stem cells, neonatal cells, umbilical cord bloodcells, fetal liver cells, adult cells, bone marrow cells, peripheralblood cells, erythroid cells, granulocyte cells, macrophage cells,granulocyte-macrophage cells, B cells, T cells, multipotent mixedlineage colony types, embryonic stem cells, mesenchymal progenitor/stemcells, mesodermal progenitor/stem cells, neural progenitor/stem cells,or nerve cells. The vertebrate can be mammalian, avian, reptilian,amphibian, osteichthyes, or chondrichthyes.

In one embodiment, the present disclosure provides a composition forpreventing or decreasing the loss of hair and/or for stimulating orincreasing hair growth or regrowth in a patient, wherein the compositioncomprises a compound according to Formula I, II, III, IIIa, IIIb, and/orIV.

In one embodiment, the present disclosure provides a composition forpreventing cochlear hair cell loss in a patient, wherein the compositioncomprises a compound according to Formula I, II, III, IIIa, IIIb, and/orIV.

One embodiment of the present disclosure provides a pharmaceuticalcomposition for the treatment of a neurodegenerative disease in apatient.

For example, the neurological disorder can be Alzheimer's disease,schizophrenia or schizo-affective disorder, bipolar disorder or unipolardisorder, depression, substance abuse, neurodegenerative disease, autismor autism spectrum disorder, or a disorder resulting from neural damagesuch as spinal injuries or brain injuries. The neurodegenerative diseasemay be, for instance, amyotrophic lateral sclerosis (Lou Gehrig'sdisease) or Parkinson's disease. In some embodiments, the disclosureprovides methods for treating a brain injury resulting from a traumaticinjury or stroke.

In some embodiments, the neurological disorder is an eye disease such asage related macular degeneration, diabetic macular edema or retinitispigmentosa.

In one embodiment, the disclosure relates to methods for (i) reducingloss of bone mass or bone density, (ii) increasing bone mass or bonedensity, (iii) maintaining bone mass or bone density and/or (iv)reducing loss of calcium from bone in a patient, the method comprising:administering to the patient a therapeutically effective amount of acompound according to Formula I, II, III, IIIa, IIIb, and/or IV. As usedin this disclosure, the term “bone mass” and “bone density” are usedinterchangeably.

In one embodiment, the disclosure relates to methods for regulatingosteoblast activity or osteoclast activity comprising the use of acompound according to Formula I, II, III, IIIa, IIIb, and/or IV.Osteoblast activity can be regulated by regulating the proliferation orfunction of osteoblasts. The function of osteoblasts and/or osteoclastscan be regulated directly or indirectly.

In one embodiment, the method is for the treatment of a bone conditionor a bone defect. For example, the bone condition being treated caninclude frailty, an osteoporotic fracture, a bone defect, childhoodidiopathic bone loss, alveolar bone loss, mandibular bone loss, bonefracture, osteotomy, bone loss associated with periodontitis, orprosthetic ingrowth. In some embodiments, the bone condition beingtreated is Paget's disease. In another embodiment, the bone conditionbeing treated is oncolytic bone disease.

In another embodiment, the disclosure relates to methods for promotinghealing of bone fractures, bone defects, craniofacial defects,otosclerosis or osteogenesis imperfecta comprising: administering to apatient in need thereof a therapeutically effective amount of a compoundaccording to Formula I, II, III, IIIa, IIIb, and/or IV.

In another embodiment, the disclosure relates to methods for bone tissueengineering comprising the use of a compound according to Formula I, II,III, IIIa, IIIb, and/or IV. In one embodiment, the cells used for bonetissue engineering are contacted with an effective amount of a compoundaccording to Formula I, II, III, IIIa, IIIb, and/or IV.

In another embodiment, the disclosure relates to the use of a compoundaccording to Formula I, II, III, IIIa, IIIb, and/or IV as a medicamentfor healing bone fractures or repairing bone defects in a mammal.

In one embodiment, the bone condition being treated is osteoporosis. Forexample, the osteoporosis being treated can be selected from the groupconsisting of: glucocorticoid-induced osteoporosis,hyperthyroidism-induced osteoporosis, immobilization-inducedosteoporosis, heparin-induced osteoporosis, andimmunosuppressive-induced osteoporosis.

In one embodiment, a compound according to Formula I, II, III, IIIa,IIIb, and/or IV is administered conjointly with an agent that increasesbone mass or prevents the loss of bone mass. In one embodiment, theagent that increases bone mass is a growth factor, a mineral, a vitamin,a hormone, a prostaglandin, an inhibitor of 15-lipoxygenase, a bonemorphogenic protein or another member of the TGF-beta superfamily whichincreases bone formation, an ACE inhibitor, a Hedgehog protein,examethasone, calcitonin, or an active fragment thereof. In oneembodiment, the agent that prevents the loss of bone mass is progestin,estrogen, an estrogen/progestin combinations, estrone, estriol, 17α- or17β-ethynyl estradiol, SB242784, polyphosphonates, bisphosphonates, oran active fragment thereof.

In one embodiment of the disclosure, a compound according to Formula I,II, III, IIIa, IIIb, and/or IV, is administered to a patient in needthereof to enhance proliferation of intestinal epithelium, for thetreatment, or as a therapeutic adjunct in the treatment, of diseasesthat compromise the intestinal epithelia, including inflammatory boweldiseases, mucositis (oral and gastrointestinal) and Celiac disease.

In another embodiment, the disclosure relates to methods for organtissue engineering comprising the use of a compound according to FormulaI, II, III, IIIa, IIIb, and/or IV. In one embodiment the cells used fororgan tissue engineering are contacted with an effective amount of acompound according to Formula I, II, III, IIIa, IIIb, and/or IV.

Some embodiments disclosed herein include a Wnt/β-catenin signalingpathway activator containing a γ-diketone core. Other embodimentsdisclosed herein include pharmaceutical compositions and methods oftreatment using one or more of the compounds provided herein.

One embodiment of a Wnt/β-catenin signaling pathway activator disclosedherein includes compounds of Formula I:

or a pharmaceutically acceptable salt thereof

In some embodiments of Formula I:

Ring A is a 7-12 membered heteroaryl, with the proviso that a carbonatom on the ring is attached to the carbonyl carbon;

Ring B is selected from the group consisting of phenyl and a 5-6membered heteroaryl, with the proviso that a carbon atom on the ring isattached to the carbonyl carbon;

R¹ is a substituent attached to Ring A and is independently selected ateach occurrence from the group consisting of H, unsubstituted —C₁₋₆alkyl, —C₁₋₃ haloalkyl, halide, —OR³, CF₃, and CN;

R² is a substituent attached to Ring B and is independently selected ateach occurrence from the group consisting of H, unsubstituted —C₁₋₆alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl, halide, —OR³, CF₃, andCN;

each R³ is independently selected from the group consisting of H,unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, and CF₃;

each R^(3b) is independently selected from the group consisting of H andunsubstituted —C₁₋₃ alkyl;

each n is an integer of 1 to 10; and

each m is an integer of 1 to 5.

Another embodiment of a Wnt/β-catenin signaling pathway activatordisclosed herein includes compounds of Formula II:

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula II:

Ring C is a 5-6 membered heteroaryl, with the proviso that a carbon atomon the ring is attached to the carbonyl carbon;

Ring D is selected from the group consisting of phenyl and a 5-6membered heteroaryl, with the proviso that a carbon atom on the ring isattached to the carbonyl carbon;

R⁴ is a substituent attached to Ring C and is independently selected ateach occurrence from the group consisting of H, unsubstituted —C₁₋₆alkyl, —C₁₋₃ haloalkyl, halide, —OR⁶, CF₃, and CN;

R⁵ is a substituent attached to Ring D and is independently selected ateach occurrence from the group consisting of H, unsubstituted —C₁₋₆alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₁₋₃ haloalkyl, halide, —OR⁶, CF₃, andCN;

each R⁶ is independently selected from the group consisting of H,unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, and CF₃;

each R^(6b) is independently selected from the group consisting of H andunsubstituted —C₁₋₃ alkyl;

each q is an integer of 1 to 4; and

each p is an integer of 1 to 5.

Another embodiment of a Wnt/β-catenin signaling pathway activatordisclosed herein includes compounds of Formula III:

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula III:

R⁷ is a substituent attached to the phenyl ring and is independentlyselected at each occurrence from the group consisting of unsubstituted—C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(9a))₂, —C₁₋₃ haloalkyl, halide, —OR⁹, CF₃,and CN;

R⁸ is a substituent attached to the phenyl ring and is independentlyselected at each occurrence from the group consisting of H,unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(9a))₂, —C₁₋₃ haloalkyl,halide, —OR⁹, CF₃, and CN;

each R⁹ is independently selected from the group consisting of H,unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl and CF₃;

each R^(9a) is independently selected from the group consisting of H andunsubstituted —C₁₋₃ alkyl; and

each q is an integer of 1 to 5.

Another embodiment of a Wnt/β-catenin signaling pathway activatordisclosed herein includes compounds of Formula IIIa:

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula IIIa:

R¹⁰ is selected from the group consisting of H, unsubstituted —C₁₋₆alkyl, —C₁₋₃ haloalkyl, halide, —OR¹³, CF₃, and CN;

R¹¹ is selected from the group consisting of unsubstituted —C₁₋₆ alkyl,—CH₂OH, —CH₂N(R^(13b))₂, —C₁₋₃ haloalkyl, halide, —OR¹³, CF₃, and CN;

R¹² is a substituent attached to the phenyl ring and is independentlyselected at each occurrence from the group consisting of H,unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(13b))₂, —C₁₋₃ haloalkyl,halide, —OR¹³, CF₃, and CN;

each R¹³ is independently selected from the group consisting ofunsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, and CF₃;

each R^(13b) is independently selected from the group consisting of Hand unsubstituted —C₁₋₃ alkyl; and

each q is an integer of 1 to 5.

Another embodiment of a Wnt/β-catenin signaling pathway activatordisclosed herein includes compounds of Formula IIIb:

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula IIIb:

R¹⁴ is selected from the group consisting of unsubstituted —C₁₋₆ alkyl,—C₁₋₃ haloalkyl, and CF₃;

R¹⁵ is selected from the group consisting of unsubstituted —C₁₋₆ alkyl,—C₁₋₃ haloalkyl, and CF₃;

R¹⁶ is a substituent attached to the phenyl ring and is independentlyselected at each occurrence from the group consisting of H,unsubstituted —C₁₋₆ alkyl, CH₂OH, —CH₂N(R^(17b))₂, —C₁₋₃ haloalkyl,halide, —OR¹⁷, CF₃, and CN;

each R¹⁷ is independently selected from the group consisting ofunsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, and CF₃;

each R^(17b) is independently selected from the group consisting of Hand unsubstituted —C₁₋₃ alkyl; and

each q is an integer of 1 to 5.

Another embodiment of a Wnt/β-catenin signaling pathway activatordisclosed herein includes compounds of Formula IV:

or a pharmaceutically acceptable salt thereof

In some embodiments of Formula IV:

Ring F is

Ring G is selected from the group consisting of

and a 5-6 membered heteroaryl R^(19d), with the proviso that a carbonatom on the ring is attached to the carbonyl carbon;

each R¹⁸ is a substituent attached to Ring F and is independentlyselected at each occurrence from the group consisting of H, —C₁₋₃haloalkyl, halide, —OR²⁰, CF₃, and CN;

R^(19a) is a substituent attached to the para position of phenyl and isselected from the group consisting of H, unsubstituted —C₂₋₆ alkyl,—CH₂OH, —CH₂N(R²¹)₂, —C₁₋₃ haloalkyl, F, Br, I, —OR²⁰, CF₃, and CN;

R^(19b) is a substituent attached to the meta or ortho position ofphenyl and is selected from the group consisting of H, unsubstituted—C₂₋₆ alkyl, —CH₂OH, —CH₂N(R²¹)₂, —C₁₋₃ haloalkyl, halide, —OR²⁰, CF₃,and CN;

R^(19c) is 2-5 substituents, each attached to the phenyl and areindependently selected at each occurrence from the group consisting ofH, —CH₂OH, —CH₂N(R²¹)₂, —C₁₋₃ haloalkyl, halide, —OR²⁰, CF₃, and CN;

R^(19d) is 1-4 substituents, each attached to the heteroaryl ring and isindependently selected at each occurrence from the group consisting ofH, —CH₂OH, —CH₂N(R²¹)₂, —C₁₋₃ haloalkyl, halide, —OR²⁰, CF₃, and CN;

each R²⁰ is independently selected from the group consisting of H,unsubstituted —C₃₋₆ alkyl, —C₁₋₃ haloalkyl, and CF₃;

each R²¹ is independently selected from the group consisting of H andunsubstituted —C₁₋₃ alkyl;

p is an integer of 1 to 13; and

r is an integer of 1 to 5.

Some embodiments include stereoisomers of a compound of Formula I, II,III, IIIa, and/or IIIb.

Some embodiments include prodrugs of a compound of Formula I, II, III,IIIa, and/or IIIb. For example, prodrugs of a compound of Formula I, II,III, IIIa, and/or IIIb can be prodrug polymer conjugates for delayedrelease or extended release.

Also provided herein are pharmaceutical compositions comprising acompound of Formula I, II, III, IIIa, and/or IIIb and a pharmaceuticallyacceptable carrier, diluent, or excipient.

Some embodiments of the present disclosure include methods to preparecompounds of Formula I, II, III, IIIa, and/or IIIb.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention, as claimed.

DETAILED DESCRIPTION

Provided herein are γ-diketones capable of activating the Wnt/β-cateninsignaling pathway. The Wnt/β-catenin signaling pathway has been found toplay a role in the differentiation and development of nerve cells forthe central nervous system, bone formation, hair follicle developmentand regeneration, and stimulation of stem cell growth, maintenance anddifferentiation.

The present disclosure relates to methods for increasing cell or tissueregeneration in a vertebrate patient. The disclosure relates to methodsfor increasing the activity of embryonic and/or adult stem cells,progenitor cells, mesenchymal progenitor/stem cells, or differentiatedcells in vivo in a vertebrate patient. The disclosure further relates tomethods for increasing cell or tissue regeneration by administering acompound according to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II,IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV toa vertebrate patient in need thereof, and increasing a stem cell,progenitor cell population, or differentiated cell in the vertebratepatient compared to the stem cell or progenitor cell, or differentiatedcell population in the vertebrate patient before treatment. In someembodiments, a method for increasing stem cell or progenitor cellpopulation can be used to repair or replace damaged tissue in avertebrate patient, wherein the cell or tissue regeneration occurs inbone, chondrocytes/cartilage, muscle, skeletal muscle, cardiac muscle,pancreatic cells, endothelial cells, vascular endothelial cells, adiposecells, liver, skin, connective tissue, hematopoietic stem cells,neonatal cells, umbilical cord blood cells, fetal liver cells, adultcells, bone marrow cells, peripheral blood cells, erythroid cells,granulocyte cells, macrophage cells, granulocyte-macrophage cells, Bcells, T cells, multipotent mixed lineage colony types, embryonic steincells, mesenchymal progenitor/stem cells, mesodermal progenitor/stemcells, neural progenitor/stem cells, or nerve cells.

Hair Growth

Compositions comprising one or more compounds according to Formula I,Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf,III, IIIa, IIIb, IIIc, IIId, and/or IV can be used to promote hairgrowth.

“Promoting hair growth” refers to maintaining, inducing, stimulating,accelerating, or revitalizing the growth of hair.

The methods of the present disclosure can be useful in the treatment ofalopecia in mammals, and as such may be used to promote, increase, orassist in the growth of hair. Patients may be male or female. The termalopecia refers to both the complete absence of hair in skin whichtypically exhibits hair growth, as well as to a loss or diminution inthe amount of hair. Multiple types and causes of alopecia are recognizedin humans, including male pattern baldness, chemotherapy induced hairloss, congenital alopecia, and alopecia areata. The treatment ofalopecia can include the treatment of skin with a total absence of hairgrowth as well as the treatment of skin having reduced or patchy hairgrowth. Successful treatment results in an increased number of hairs.

Patients to be treated according to the disclosure include humanpatients as well as other mammalian patients, such as dogs, cats, mice,rats, goats, llamas, minks, seals, beavers, ermines, and sheep. Patientscan be treated for hair loss or to enhance the growth of hair, forexample to increase wool or pelt production.

“Treating alopecia” refers to (i) preventing alopecia in an animal whichmay be predisposed to alopecia, (ii) inhibiting, retarding or reducingalopecia, (iii) promoting hair growth, and/or (iv) prolonging the anagenphase of the hair cycle.

A method for promoting hair growth in accordance with the presentdisclosure can include applying an effective amount of a compoundaccording to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV, or apharmacologically acceptable salt thereof, to the skin of mammals. Forexample, the compound can be applied to a human scalp.

Cochlear Hair Cell Loss

Compositions comprising one or more compounds according to Formula I,Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf,III, IIIa, IIIb, IIIc, IIId, and/or IV can be used to promoteregeneration of lost or damaged sensory hair cells.

“Promoting the regeneration of sensory hair cells” refers tomaintaining, inducing, stimulating, accelerating, or revitalizing thegrowth of sensory hair cells.

The methods of the present disclosure are useful in the treatment ofpresbycusis in mammals, and as such may be used to promote, increase, orassist in the growth of cochlea hair cells. Mammalian cochlear haircells come in two anatomically and functionally distinct types: theouter and inner hair cells. Patients may be male or female. Presbycusiscan be caused by the slow loss of hearing that occurs as a result ofageing, after repeated exposure to loud noises, or as a symptom ofcertain medical conditions or medications. Multiple types and causes ofpresbycusis are recognized in humans, including, for example,arteriosclerosis (may diminish vascularity of the cochlea, therebyreducing its oxygen supply), diabetes mellitus (may cause vasculitis andendothelial proliferation in the blood vessels of the cochlea, therebyreducing its blood supply), poor diet (increased intake of saturated fatmay accelerate atherosclerotic changes), stress, heart disease, diabetesblood vessel complications, high blood pressure, smoking (postulated toaccentuate atherosclerotic changes in blood vessels), and viral orbacterial infections. Drugs, medications, substances, or toxins that cancause presbycusis as a symptom include, for example, aminoglycosides(gentamycin, streptomycin, etc.) and other antibiotics (macrolides andvancomycin), antineoplastic agents (platinum-based compounds cisplatinand carboplatin), salicylates (aspirin), quinine, and loop diuretics(ethacrynic acid, furosemide, bumetanide, etc.).

The term treating presbycusis refers to both the treatment of patientswith total hearing loss as well as partial hearing loss. Successfultreatment results in an improvement in a patient's hearing.

A method for promoting the regeneration of sensory hair cells inaccordance with the present disclosure can include applying an effectiveamount of a compound according to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig,Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId,and/or IV, or a pharmacologically acceptable salt thereof, in the ear ofmammals. For example, the compound may be applied to the inner ear, orvia intratympanic injection to the round window membrane or vicinity ofthe round window membrane.

Neurological Disorder

Compounds according to the present disclosure can modulate the cellularfate of neural stem cells and promote the differentiation of theseneural precursors to functional neurons and glial cells.

Compositions comprising one or more compounds according to Formula I,Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf,III, IIIc, IIIb, IIIc, IIId, and/or IV can be used to treatneurodegenerative diseases.

Non-limiting examples of neurodegenerative diseases include Alzheimer'sdisease, schizophrenia or schizo-affective disorder, bipolar disorder orunipolar disorder, depression, substance abuse, neurodegenerativedisease, autism or autism spectrum disorder, or a disorder resultingfrom neural damage such as spinal injuries or brain injuries. Theneurodegenerative disease may be, for instance, amyotrophic lateralsclerosis (Lou Gehrig's disease) or Parkinson's disease.

Other non-limiting examples of neurodegenerative diseases include eyediseases including, but not limited to, wet age-related maculardegeneration, dry age-related macular degeneration, geographic atrophy,diabetic retinopathy, diabetic macular edema, retinal detachment,retinal degeneration, retinal vein occlusion, retinopathy ofprematurity, retinitis pigmentosa, retinopathies, Leber congenitalamaurosis and glaucoma.

The disclosure also provides methods for treating brain injury resultingfrom a traumatic injury or stroke.

Another aspect of the disclosure is a method for enhancing neuralprogenitor proliferation and differentiation by contacting a neuralprogenitor cell with a compound according to Formula I, Ia, Ib, Ic, Id,Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb,IIIc, IIId, and/or IV in an effective amount to enhance neuralprogenitor proliferation and differentiation.

In one aspect the disclosure provides a method for enhancing nervegeneration, by contacting a nerve with a compound according to FormulaI, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf,III, IIIa, IIIb, IIIc, IIId, and/or IV in an effective amount to enhancenerve generation.

In another aspect, the present disclosure provides a method for treatinga neurodegenerative disease in a patient requiring such treatment, whichcomprises administering an effective amount of a compound of Formula I,Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf,III, IIIa, IIIb, IIIc, IIId, and/or IV, or a pharmaceutically acceptablesalt thereof.

The compounds according to the present disclosure may be administeredalone or in combination with another active agent. In one embodiment, acompound provided herein can be co-administered with anacetylcholinesterase inhibitor (e.g. Aricept) for Alzheimer's disease orL-DOPA for Parkinson disease.

Bone Formation

Compositions comprising one or more compounds of Formula I, Ia, Ib, Ic,Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa,IIIb, IIIc, IIId, and/or IV can be used to treat, prevent or alleviatebone conditions. The present disclosure provides methods for (i)reducing loss of bone mass, (ii) increasing bone mass, (iii) maintainingbone mass, and/or (iv) reducing loss of calcium from bone, comprising:administering to a patient in need thereof a therapeutically effectiveamount of a compound according to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig,Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId,and/or IV. The method could be used for treating, preventing, ordelaying a bone condition. The disclosure further provides a method forpromoting the healing of bone fractures or bone defects comprising:administering to a patient a therapeutically effective amount of acompound according to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II,IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV.Any of the above mentioned methods can involve the conjointadministration of an agent that increases bone mass or prevents the lossof bone mass.

The disclosure also provides for the use of a compound according toFormula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId,IIe, IIf, III, IIIa, IIIc, IIId, and/or IV as a medicament for treating,preventing or delaying a bone condition.

As used herein, the term “bone condition” includes any condition whereit is desirable to increase bone mass or bone density and/or prevent theloss of bone mass or bone density. A bone condition includes anycondition that increases osteoclast number, increases osteoclastactivity, increases bone resorption, increases marrow fibrosis, oralters the calcium content of bone.

Non-limiting examples of bone conditions include metabolic boneconditions such as renal osteodystrophy, primary forms of osteoporosis(e.g., postmenopausal and senile osteoporosis), and secondary forms ofosteoporosis that develop as a result of an underlying disease state.For example, osteoporosis can develop in patients that have endocrinedisorders such as hyperparathyroidism, hypo- and hyperthyroidism,hypogonadism, hypercalcemia due to malignancy, pituitary tumors, type Idiabetes, or Addison's disease. Neoplasias such as multiple myeloma andcarcinomatosis also can lead to development of osteoporosis. Inaddition, gastrointestinal problems such as malnutrition, malabsorption,hepatic insufficiency, and vitamin C or D deficiencies, and chronicadministration of drugs such as anticoagulants, chemotherapeutics,corticosteroids, anticonvulsants, and alcohol can lead to development ofosteoporosis.

Non-limiting examples of bone conditions also include osteonecrosis,osteoarthritis, rheumatoid arthritis, Paget's disease, osteogenesisimperfecta, chronic hyperparathyroidism, hyperthyroidism, Gorham-Stoutdisease, McCune-Albright syndrome, and alveolar ridge bone loss.

Bone conditions can also include, without limitation, conditionsresulting in bone loss, for example, cancers and tumors (such asosteosarcoma and multiple myeloma), renal disease (including acute renalfailure, chronic renal failure, renal bone dystrophy and renalreperfusion injury), kidney disease, and premature ovarian failure.

Endocrine disorders, vitamin deficiencies and viral infections also canlead to the development of bone conditions that can be treated asdescribed herein. An example of a bone condition caused by a nutritionaldisorder is osteomalacia, a nutritional disorder caused by a deficiencyof vitamin D and calcium. It is referred to as “rickets” in children,and “osteomalacia” in adults. It is marked by a softening of the bones(due to impaired mineralization, with excess accumulation of osteoid),pain, tenderness, muscle wasting and weakness, anorexia, and overallweight loss. It can result from malnutrition, repeated pregnancies andlactation (exhausting or depleting vitamin D and calcium stores), andvitamin D resistance.

Bone conditions include conditions resulting from the treatment of apatient with drugs, for example the osteopenia resulting from thetreatment with Cyclosporin A or FK506.

Bone conditions also include bone fractures, bone trauma, conditionsassociated with post-traumatic bone surgery, post-prosthetic jointsurgery, post-plastic bone surgery, post-dental surgery, bonechemotherapy, post-dental surgery, and bone radiotherapy. Fracturesinclude all types of microscopic and macroscopic fractures. Examples offractures includes avulsion fracture, comminuted fracture, transversefracture, oblique fracture, spiral fracture, segmental fracture,displaced fracture, impacted fracture, greenstick fracture, torusfracture, fatigue fracture, intra-articular fracture (epiphysealfracture), closed fracture (simple fracture), open fracture (compoundfracture), and occult fracture.

Other non-limiting examples of bone conditions include bone deformation,spinal deformation, prosthesis loosening, bone dysplasia, scoliosis,periodontal disease and defects, tooth repair, and fibrous osteitis.

The disclosure also provides a method for treating a patient with atherapeutically effective amount of a compound according to Formula I,Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf,III, IIIa, IIIb, IIIc, IIId, and/or IV, wherein the patient is in needof bone repair following surgery, such as cranio-maxillofacial repairfollowing tumor removal, surgical bone reconstruction followingtraumatic injury, repair of hereditary or other physical abnormalities,and promotion of bone healing in plastic surgery.

The disclosure also provides a method for treating a patient with atherapeutically effective amount of a compound according to Formula I,Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf,III, IIIa, IIIb, IIIc, IIId, and/or IV, wherein the patient is in needof bone repair after receiving an implant (including joint replacementsand dental implants), prosthesis or a bone graft.

The disclosure also provides a method for treating a patient with atherapeutically effective amount of a compound according to Formula I,Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf,III, IIIa, IIIb, IIIc, IIId, and/or IV, wherein the patient: a) is inneed of increased bone density or bone healing; b) has undergone or ispresently undergoing corticosteroid therapy, dialysis, chemotherapy forpost-menopausal bone loss, radiation therapy for cancer, or hormonereplacement therapy; c) is immobilized or subjected to extended bed restdue to bone injury; d) suffers from alcoholism, diabetes,hyperprolactinemia, anorexia nervosa, primary and secondary amenorrhea,or oophorectomy; e) suffers from renal failure; f) is 50 years or older;or g) is a female.

The disclosure also provides a method for treating a patient with atherapeutically effective amount of a compound according to Formula I,Ia, Ib, IIc, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf,III, IIIa, IIIb, IIIc, IIId, and/or IV, wherein the patient is affectedby a disease selected from arterial calcification, ankylosingspondylitis, ossification of the posterior longitudinal ligament,myositis ossificans, diffuse idiopathic skeletal hyperostosis, calcifictendonitis, rotator cuff disease of the shoulders, bone spurs, cartilageor ligament degeneration due to hydroxyapatite crystal deposition, andchondrocalcinosis.

The disclosure also provides a method for treating a patient with atherapeutically effective amount of a compound according to Formula I,Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf,III, IIIa, IIIb, IIIc, IIId, and/or IV conjointly with an agent thatincreases bone mass or prevents the loss of bone mass. In oneembodiment, the agent that increases bone mass is a growth factor, amineral, a vitamin, a hormone, a prostaglandin, an inhibitor of15-lipoxygenase, a bone morphogenic protein or another member of theTGF-beta superfamily which increases bone formation, an ACE inhibitor, aHedgehog protein, examethasone, calcitonin, or an active fragmentthereof. In one embodiment, the agent that prevents the loss of bonemass is progestin, estrogen, an estrogen/progestin combinations,estrone, estriol, 17α- or 17β-ethynyl estradiol, SB242784,polyphosphonates, bisphosphonates, or an active fragment thereof

Intestinal Diseases

Compounds according to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii,II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IVcan also administered for the treatment of gastrointestinalinflammation. “Gastrointestinal inflammation” as used herein refers toinflammation of a mucosal layer of the gastrointestinal tract, andencompasses acute and chronic inflammatory conditions. Acuteinflammation is generally characterized by a short time of onset andinfiltration or influx of neutrophils.

“Chronic gastrointestinal inflammation” refers to inflammation of themucosal of the gastrointestinal tract that is characterized by arelatively longer period of onset, is long-lasting (e. g., from severaldays, weeks, months, or years and up to the life of the patient), and isassociated with infiltration or influx of mononuclear cells and can befurther associated with periods of spontaneous remission and spontaneousoccurrence. Thus, patients with chronic gastrointestinal inflammationmay be expected to require a long period of supervision, observation, orcare. “Chronic gastrointestinal inflammatory conditions” (also referredto as “chronic gastrointestinal inflammatory diseases”) having suchchronic inflammation include, but are not necessarily limited to,inflammatory bowel disease (IBD), colitis induced by environmentalinsults (e. g., gastrointestinal inflammation (e. g., colitis) caused byor associated with (e. g., as a side effect) a therapeutic regimen, suchas administration of chemotherapy, radiation therapy, and the like),colitis in conditions such as chronic granulomatous disease, celiacdisease, celiac sprue (a heritable disease in which the intestinallining is inflamed in response to the ingestion of a protein known asgluten), food allergies, gastritis, infectious gastritis orenterocolitis (e. g., Helicobacter pylori-infected chronic activegastritis) and other forms of gastrointestinal inflammation caused by aninfectious agent, and other like conditions.

As used herein, “inflammatory bowel disease” or “IBD” refers to any of avariety of diseases characterized by inflammation of all or part of theintestines. Examples of inflammatory bowel diseases include, but are notlimited to, Crohn's disease and ulcerative colitis. Reference to IBDthroughout the specification is used throughout the specification as anexample of the gastrointestinal inflammatory conditions provided herein,and is not meant to be limiting.

Compounds according to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii,II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IVcan be administered to a patient prior to onset of more severe symptoms(e.g., prior to onset of an acute inflammatory attack), or after onsetof acute or chronic symptoms (e.g., after onset of an acute inflammatoryattack). As such, the agents can be administered at any time, and may beadministered at any interval. In one embodiment, a compound according toFormula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId,IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV can be administeredabout 8 hours, about 12 hours, about 24 hours, about 2 days, about 4days, about 8 days, about 16 days, about 30 days or 1 month, about 2months, about 4 months, about 8 months, or about 1 year after theinitial onset of gastrointestinal inflammation-associated symptomsand/or after diagnosis of gastrointestinal inflammation in the patient.

When multiple doses are administered, subsequent doses can beadministered within about 16 weeks, about 12 weeks, about 8 weeks, about6 weeks, about 4 weeks, about 2 weeks, about 1 week, about 5 days, about72 hours, about 48 hours, about 24 hours, about 12 hours, about 8 hours,about 4 hours, or about 2 hours or less of the previous dose. In oneembodiment, does are administered at intervals ranging from at leastevery two weeks to every four weeks (e.g., monthly intervals) in orderto maintain the maximal desired therapeutic effect (e.g., to provide formaintenance of relief from IBD-associated symptoms).

Compounds according to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii,IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV canalso be administered for the treatment of mucositis. “Mucositis” as usedherein refers to inflammatory and/or ulcerative lesions anywhere alongthe gastrointestinal (GI) tract. Infectious disease, immune deficiency,and medications can be causative. One of the major causes of mucositisis high-dose cancer therapy. In some embodiments, the mucositis isalimentary tract mucositis or oral mucositis. Alimentary tract mucositisrefers to the expression of mucosal injury across the continuum of oraland gastrointestinal mucosa, from the mouth to the anus. Oral mucositisrefers to the particular inflammation and ulceration that occurs in themouth. Oral mucositis is a common and often debilitating complication ofcancer treatment.

Regenerative Medicine

According to the present disclosure, pluripotent stem cells (PS cells)are capable of differentiating into any cell type of the body and retainthe property of self-renewal, thereby providing a potentially unlimitedsource of new healthy tissue. In this regard, PS cells have attracted agreat deal of attention due to their potential use for tissue and cellbased therapies. PS cell derivation originally depended on the viralexpression of the four transcription factors i.e. Oct4, Sox2, Klf4 andc-Myc. However, recent efforts to avoid genetic manipulation with theultimate goal of clinical applications have led researchers to furtherdefine the signaling pathways involved in cell reprogramming with theaim of replacing ectopic gene expression with proteins or smallmolecules. Wnt/β-catenin signaling in particular has been highlighted asone of the key pathways in this process.

Somatic cells as referred to in the present disclosure refer to cellsthat have reached differentiation into cells that compose various organsof the body. In some embodiments, two or more somatic cells may be usedin the methods described herein. For example, a combination of anepithelial cell line and mesenchymal cells, a combination of endothelialcells and mesenchymal cells, or a combination of epithelial cells andmesenchymal cells can be used.

There are no particular limitations on organs capable of being formed bythe somatic cells provided herein. Non-limiting examples include variousorgans such as hair follicle, lung, kidney, liver, pancreas, spleen,heart, gallbladder, small intestine, colon, large intestine, joint,bone, tooth, blood vessel, lymph duct, cornea, cartilage, olfactoryorgan, or auditory organ.

Various mammals can be used without limitation as the origin of thecells provided herein depending on the ultimate intended purpose of thecells. For example, mammals include chimpanzees, other primates,domestic animals such as dogs or cats, farm animals such as cows, pigs,horses, sheep or goats, laboratory animals such as rabbits, rats, miceor guinea pigs. In some embodiments, the mammals are nude mice, SCIDmice, or nude rats. In addition, combinations of cells can includehomogeneous combinations or heterogeneous combinations. In someembodiments, the combination is a homogeneous combination. In someembodiments, culturing somatic cells of one or more types ofdifferentiated somatic cells as described above can be combine with oneor more Wnt/β-catenin signaling pathway activators according to FormulaI, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf,III, IIIa, IIIb, IIIc, IIId, and/or IV.

DEFINITIONS

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art to which this disclosure belongs. All patents, applications,published applications, and other publications are incorporated byreference in their entirety. In the event that there is a plurality ofdefinitions for a term herein, those in this section prevail unlessstated otherwise.

As used herein, “alkyl” means a branched, or straight chain chemicalgroup containing only carbon and hydrogen, such as methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,n-pentyl, iso-pentyl, sec-pentyl and neo-pentyl. Alkyl groups can eitherbe unsubstituted or substituted with one or more substituents. Alkylgroups can be saturated or unsaturated (e.g., containing —C═C— orsubunits), at one or several positions. Typically, alkyl groups willcomprise 1 to 9 carbon atoms (for example, 1 to 6 carbon atoms, 1 to 4carbon atoms, or 1 to 2 carbon atoms).

As used herein, “carbocyclyl” means a cyclic ring system containing onlycarbon atoms in the ring system backbone, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. Carbocyclyls mayinclude multiple fused rings. Carbocyclyls may have any degree ofsaturation provided that at least one ring in the ring system is notaromatic. Carbocyclyl groups can either be unsubstituted or substitutedwith one or more substituents. Typically, carbocyclyl groups willcomprise 3 to 10 carbon atoms, for example, 3 to 6 carbon atoms.

As used herein, “lower alkyl” means a subset of alkyl having 1 to 3carbon atoms, which is linear or branched. Examples of lower alkylsinclude methyl, ethyl, n-propyl and isopropyl. Likewise, radicals usingthe terminology “lower” refer to radicals having 1 to about 3 carbons inthe alkyl portion of the radical.

As used herein, “aryl” means an aromatic ring system containing asingle-ring (e.g., phenyl) or multiple condensed rings (e.g., naphthylor anthryl) with only carbon atoms present in the ring backbone. Arylgroups can either be unsubstituted or substituted with one or moresubstituents. In some embodiments, the aryl is phenyl.

As used herein, “arylalkyl” means an aryl-alkyl- group in which the aryland alkyl moieties are as previously described. Preferred arylalkylgroups contain a C₁₋₄ alkyl moiety. Exemplary arylalkyl groups includebenzyl and 2-phenethyl.

As used herein, the term “heteroaryl” means a mono-, bi-, tri- orpolycyclic group having 5 to 14 ring atoms, alternatively 5, 6, 9, or 10ring atoms; having 6, 10, or 14 pi electrons shared in a cyclic array;wherein at least one ring in the system is aromatic, and at least onering in the system contains one or more heteroatoms independentlyselected from the group consisting of N, O, and S. Heteroaryl groups caneither be unsubstituted or substituted with one or more substituents.Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl,oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl,isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl,triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl,benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl,isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl,pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl,quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl,pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine,pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane,2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole,2,3-dihydrobenzofuran, 2,3-dihydrobenzo[b][1,4]oxathiine, and others.

As used herein, “heteroarylalkyl” means a heteroaryl-alkyl- group inwhich the heteroaryl and alkyl moieties are as previously described.Preferred heteroarylalkyl groups contain a C₁₋₄ alkyl moiety. Exemplaryheteroarylalkyl groups include pyridylmethyl.

As used herein, “acyl” means an H—CO— or alkyl-CO—, carbocyclyl-CO—,aryl-CO—, heteroaryl-CO—, or heterocyclyl-CO— group wherein the alkyl,carbocyclyl, aryl or heterocyclyl group is as herein described. In someembodiments, acyls contain a lower alkyl. Exemplary alkyl acyl groupsinclude formyl, acetyl, propanoyl, 2-methylpropanoyl, t-butylacetyl,butanoyl, and palmitoyl.

As used herein, “alkoxycarbonyl” means an alkyl-O—CO— group in which thealkyl group is as described herein. Exemplary alkoxycarbonyl groupsinclude methoxy- and ethoxycarbonyl.

As used herein, “alkoxy” means an alkyl-O— group in which the alkylgroup is as described herein. Exemplary alkoxy groups includedifluoromethoxy, methoxy, trifluoromethoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, s-butoxy, t-butoxy, pentoxy, hexoxy and heptoxy,and also the linear or branched positional isomers thereof.

As used herein, “halo”, “halide” or “halogen” is a chloro, bromo,fluoro, or iodo atom radical. In some embodiments, a halo is a chloro,bromo or fluoro. For example, a halo can be fluoro.

As used herein, “haloalkyl” means a hydrocarbon substituent, which is alinear or branched or cyclic alkyl, alkenyl or alkynyl substituted withone or more chloro, bromo, fluoro, or iodo atom(s). In some embodiments,a haloalkyl is a fluoroalkyls, wherein one or more of the hydrogen atomshave been substituted by fluoro. In some embodiments, haloalkyls are of1 to about 3 carbons in length (e.g., 1 to about 2 carbons in length or1 carbon in length). The term “haloalkylene” means a diradical variantof haloalkyl, and such diradicals may act as spacers between radicals,other atoms, or between a ring and another functional group.

As used herein, “heterocyclyl” means a nonaromatic cyclic ring systemcomprising at least one heteroatom in the ring system backbone.Heterocyclyls may include multiple fused rings. Heterocyclyls may besubstituted or unsubstituted with one or more substituents. In someembodiments, heterocycles have 5-7 members. In six membered monocyclicheterocycles, the heteroatom(s) are selected from one up to three of O,N or S, and wherein when the heterocycle is five membered, it can haveone or two heteroatoms selected from O, N, or S. Examples ofheterocyclyl include azirinyl, aziridinyl, azetidinyl, oxetanyl,thietanyl, 1,4,2-dithiazolyl, dihydropyridinyl, 1,3-dioxanyl,1,4-dioxanyl, 1,3-dioxolanyl, morpholinyl, thiomorpholinyl, piperazinyl,pyranyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl, oxazinyl,thiazinyl, thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl,isoxazolidinyl, piperidinyl, pyrazolidinyl imidazolidinyl,thiomorpholinyl, and others.

The term “substituted” refers to moieties having substituents replacinga hydrogen on one or more non-hydrogen atoms of the molecule. It will beunderstood that “substitution” or “substituted with” includes theimplicit proviso that such substitution is in accordance with permittedvalence of the substituted atom and the substituent, and that thesubstitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, etc. Substituents can include, for example, analkyl, a halide, a hydroxyl, a carbonyl (such as a carboxyl, analkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as athioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, aphosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine,an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, asulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, acarbocyclyl, a heterocyclyl, an arylalkyl, a heteroarylalkyl, an aryl,or heteroaryl moiety.

As used herein, when two groups are indicated to be “linked” or “bonded”to form a “ring”, it is to be understood that a bond is formed betweenthe two groups and may involve replacement of a hydrogen atom on one orboth groups with the bond, thereby forming a carbocyclyl, heterocyclyl,aryl, or heteroaryl ring. The skilled artisan will recognize that suchrings can and are readily formed by routine chemical reactions. In someembodiments, such rings have from 3-7 members, for example, 5 or 6members.

The skilled artisan will recognize that some structures described hereinmay be resonance forms or tautomers of compounds that may be fairlyrepresented by other chemical structures, even when kinetically, theartisan recognizes that such structures are only a very small portion ofa sample of such compound(s). Such compounds are clearly contemplatedwithin the scope of this disclosure, though such resonance forms ortautomers are not represented herein.

The compounds provided herein may encompass various stereochemicalforms. The compounds also encompass diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds. Separation ofthe individual isomers or selective synthesis of the individual isomersis accomplished by application of various methods which are well knownto practitioners in the art. Unless otherwise indicated, when adisclosed compound is named or depicted by a structure withoutspecifying the stereochemistry and has one or more chiral centers, it isunderstood to represent all possible stereoisomers of the compound.

The term “administration” or “administering” refers to a method ofproviding a dosage of a compound or pharmaceutical composition to avertebrate or invertebrate, including a mammal, a bird, a fish, or anamphibian, where the method is, e.g., orally, subcutaneously,intravenously, intralymphatic, intranasally, topically, transdermally,intraperitoneally, intramuscularly, intrapulmonarily, vaginally,rectally, ontologically, neuro-ontologically, intraocularly,subconjuctivally, via anterior eye chamber injection, intravitreally,intraperitoneally, intrathecally, intracystically, intrapleurally, viawound irrigation, intrabuccally, intra-abdominally, intra-articularly,intra-aurally, intrabronchially, intracapsularly, intrameningeally, viainhalation, via endotracheal or endobronchial instillation, via directinstillation into pulmonary cavities, intraspinally, intrasynovially,intrathoracically, via thoracostomy irrigation, epidurally,intratympanically, intracisternally, intravascularly,intraventricularly, intraosseously, via irrigation of infected bone, orvia application as part of any admixture with a prosthetic device. Themethod of administration can vary depending on various factors, e.g.,the components of the pharmaceutical composition, the site of thedisease, the disease involved, and the severity of the disease.

A “diagnostic” as used herein is a compound, method, system, or devicethat assists in the identification or characterization of a health ordisease state. The diagnostic can be used in standard assays as is knownin the art.

The term “pharmaceutically acceptable carrier”, “pharmaceuticallyacceptable diluent” or “pharmaceutically acceptable excipient” includesany and all solvents, co-solvents, complexing agents, dispersion media,coatings, isotonic and absorption delaying agents and the like which arenot biologically or otherwise undesirable. The use of such media andagents for pharmaceutically active substances is well known in the art.Except insofar as any conventional media or agent is incompatible withthe active ingredient, its use in the therapeutic compositions iscontemplated. Supplementary active ingredients can also be incorporatedinto the compositions. In addition, various adjuvants such as arecommonly used in the art may be included. These and other such compoundsare described in the literature, e.g., in the Merck Index, Merck &Company, Rahway, N.J. Considerations for the inclusion of variouscomponents in pharmaceutical compositions are described, e.g., in Gilmanet al. (Eds.) (2010); Goodman and Gilman's The Pharmacological Basis ofTherapeutics, 12th Ed., The McGraw-Hill Companies.

The term “pharmaceutically acceptable salt” refers to salts that retainthe biological effectiveness and properties of the compounds providedherein and, which are not biologically or otherwise undesirable. In manycases, the compounds provided herein are capable of forming acid and/orbase salts by virtue of the presence of amino and/or carboxyl groups orgroups similar thereto. Pharmaceutically acceptable acid addition saltscan be formed with inorganic acids and organic acids. Inorganic acidsfrom which salts can be derived include, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike. Organic acids from which salts can be derived include, forexample, acetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Pharmaceutically acceptable base additionsalts can be formed with inorganic and organic bases. Inorganic basesfrom which salts can be derived include, for example, sodium, potassium,lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese,aluminum, and the like; particularly preferred are the ammonium,potassium, sodium, calcium, and magnesium salts. Organic bases fromwhich salts can be derived include, for example, primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, basic ion exchange resins, and thelike, specifically such as isopropylamine, trimethylamine, diethylamine,triethylamine, tripropylamine, and ethanolamine. Many such salts areknown in the art, for example, as described in WO 87/05297.

“Solvate” refers to the compound formed by the interaction of a solventand a Wnt pathway activator as provided herein or a salt thereof.Suitable solvates are pharmaceutically acceptable solvates includinghydrates.

The term “patient” as used herein, means a human or a non-human mammal,e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, anon-human primate, or a bird, e.g., a chicken, as well as any othervertebrate or invertebrate. In some embodiments, the patient is a human.

The term “mammal” is used in its usual biological sense. Thus, itspecifically includes humans, cattle, horses, monkeys, dogs, cats,mouse, rat, a cow, sheep, pig, goat, and non-human primate but alsoincludes many other species.

The term “vertebrate” is used in its usual biological sense. Thus, itspecifically includes the classes' agnatha (jawless fishes),chondrichthyes (cartilaginous fishes), osteichthyes (bony fishes),amphibia (amphibians), reptilia (reptiles), ayes (birds) and mammalia(mammals).

By “therapeutically effective amount” or “pharmaceutically effectiveamount” of a compound as provided herein is one which is sufficient toachieve the desired physiological effect and may vary according to thenature and severity of the disease condition, and the potency of thecompound. “Therapeutically effective amount” is also intended to includeone or more of the compounds of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig,Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId,and/or IV in combination with one or more other agents that areeffective to treat Wnt related diseases and/or conditions. Thecombination of compounds can be a synergistic combination. Synergy, asdescribed, for example, by Chou and Talalay, Advances in EnzymeRegulation (1984), 22, 27-55, occurs when the effect of the compoundswhen administered in combination is greater than the additive effect ofthe compounds when administered alone as a single agent. In general, asynergistic effect is most clearly demonstrated at sub-optimalconcentrations of the compounds. It will be appreciated that differentconcentrations may be employed for prophylaxis than for treatment of anactive disease. This amount can further depend upon the patient'sheight, weight, sex, age and medical history.

A therapeutic effect relieves, to some extent, one or more of thesymptoms of the disease, and can include curing a disease. “Curing”means that the symptoms of a disease are eliminated. However, certainlong-term or permanent effects of the disease may exist even after acure is obtained (such as extensive tissue damage).

“Treat,” “treatment,” or “treating,” as used herein refers toadministering a compound or pharmaceutical composition as providedherein for therapeutic purposes. The term “therapeutic treatment” refersto administering treatment to a patient already suffering from a diseasethus causing a therapeutically beneficial effect, such as amelioratingexisting symptoms, preventing additional symptoms, ameliorating orpreventing the underlying metabolic causes of symptoms, postponing orpreventing the further development of a disorder, and/or reducing theseverity of symptoms that will or are expected to develop.

The expression “compound-eluting” shall be understood to refer to anyand all mechanisms, e.g., diffusion, migration, permeation, and/ordesorption by which the compound(s) incorporated in the compound-elutingmaterial or coating pass therefrom over time into the surrounding bodytissue.

The expression “controlled release” encompasses many types of controlledrelease, including, for example, immediate release, pulsatile release,slow release, sustained release, and delayed release, to achieve adesired compound delivery profile.

The expression “compound-eluting material” and/or “compound-elutingcoating” and/or “controlled release material” shall be understood hereinto mean any natural, synthetic, or semi-synthetic material into whichone or more compounds can be incorporated and from which incorporatedcompound(s) are capable of eluting over time. Materials for the deliveryof a compound include a wide range of polymers and small-moleculematrices. For many compound-polymer systems, the release of the compoundis dominated by the diffusion of the compound through a polymer matrix.Polymer materials for compound delivery coatings may be durable ordegradable [see, e.g., Current Pharmaceutical Design (2010), 16(36),3978-3988]. Durable polymers are used in devices such as Cordis Cypher,Boston Scientific Taxus, Boston Scientific Promus, Abbott Xience, andMedtronic Resolute stents. Durable polymers can allow for longerdelivery times and the underlying matrix does not change over time.Degradable polymer coatings are used in devices such as OrbusNeich Combostent. These materials enable control over the release of a compound byboth diffusion (similar to durable systems) and degradation of thepolymer, which can change the polymer Tg, coating thickness, andencapsulation of the compound over time. Some devices utilize bothdurable and biodegradable coatings, such as a stent coated on the innerand outer lumen for two different compound delivery mechanisms in asingle device. In some embodiments, water insoluble/hydrophobiccompounds may be coated directly onto the device with or without one ormore additives [U.S. Pat. Appl. Publ. (2004), US20040224003 & PCT Int.Appl. (2013), WO/2013/169724].

The following abbreviations have the indicated meanings:

-   -   AD=Alzheimer's disease    -   APC=adenomatous polyposis coli    -   L-DOPA=L-3,4-dihydroxyphenylalanine    -   Lef=lymphoid enhancing factor    -   MMTV=mouse mammary tumor virus    -   SCID=severe combined immunodeficiency    -   TCF=T-cell factor    -   TGF=transforming growth factor    -   Wnt=wingless-type MMTV integration site family member

Compounds

The compounds and compositions described herein are capable ofactivating the Wnt/β-catenin signaling pathway. The Wnt/β-cateninsignaling pathway has been found to play a role in the differentiationand development of nerve cells for the central nervous system, boneformation, hair follicle development and regeneration, and stimulationof stem cell growth, maintenance, and differentiation.

Some embodiments of the present disclosure include compounds of Formula(I):

or salts, pharmaceutically acceptable salts, or prodrugs thereof.

In some embodiments of Formula I, Ring A is a 7-12 membered heteroaryl,wherein a carbon atom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula I, Ring B is selected from the groupconsisting of phenyl and a 5-6 membered heteroaryl, with the provisothat a carbon atom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula I, R¹ is a substituent attached to Ring Aand is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR³, CF₃, and CN.

In some embodiments of Formula I, R² is a substituent attached to Ring Band is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂,—C₁₋₃ haloalkyl, halide, —OR³, CF₃, and CN.

In some embodiments of Formula I, each R³ is independently selected fromthe group consisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl,and CF₃.

In some embodiments of Formula I, each R^(3b) is independently selectedfrom the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula I, each n is an integer of 1 to 10.

In some embodiments of Formula I, each m is an integer of 1 to 5.

In some embodiments of Formula I, there is the proviso that a compoundof Formula I is not a compound selected from the group consisting of:

with the proviso that the compound of Formula I is not a compoundselected from the group consisting of:

In some embodiments of Formula I, Ring A is a 9-membered bicyclicheteroaryl ring containing 1-3 heteroatoms selected from the groupconsisting of N, O, and S.

In some embodiments of Formula I, Ring A is a 10-membered bicyclicheteroaryl ring containing 1-3 heteroatoms selected from the groupconsisting of N, O, and S.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R¹ is selected from the group consisting of H, F, Cl, Me, OMe, OH,CF₃, and CN.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R¹ is H.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R¹ is a halide.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orR¹ is F.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R¹ is Cl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R¹ is Me.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R¹ is OH.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R¹ is OMe.

In some embodiments of Formula I, N, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R¹ is CF₃.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R¹ is CN.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, n is an integer from 1-8.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, n is an integer from 1-6.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, n is an integer from 1-4.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, n is an integer from 1-2.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R¹ is F; and n is 1.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R¹ is F; and n is an integer from 1-2.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R¹ is F; and n is an integer from 3-4.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R¹ is OH; and n is an integer from 1-2.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R¹ is OMe; and n is an integer from 1-2.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R¹ is —C₁₋₂ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R¹ is —C₁₋₃ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R¹ is —C₁₋₄ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R¹ is —C₁₋₅ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R¹ is —C₁₋₆ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R¹ is —C₂₋₆ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R¹ is —C₃₋₆ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R¹ is —C₄₋₆ alkyl.

In some embodiments, each R¹ is the same.

In some embodiments of Formula I, Ring A is selected from the groupconsisting of:

wherein, unless otherwise designated, the carbonyl carbon of Formula Ican form a bond with any unsubstituted carbon on Ring A.

In some embodiments of Formula I, Ring A is selected from the groupconsisting of:

wherein the carbonyl carbon of Formula I can form a bond with anyunsubstituted carbon on Ring A.

In some embodiments of Formula I, Ring A is selected from the groupconsisting of:

wherein the carbonyl carbon of Formula I can form a bond with anyunsubstituted carbon on the Ring A.

In some embodiments of Formula I, Ring A is selected from the groupconsisting of:

wherein the carbonyl carbon of Formula I can form a bond with anyunsubstituted carbon on the Ring A.

In some embodiments of Formula I, Ring A is selected from the groupconsisting of

wherein the carbonyl carbon of Formula I can form a bond with anyunsubstituted carbon on the Ring A.

In some embodiments of Formula I, Ring A is selected from the groupconsisting of

wherein the carbonyl carbon of Formula I can form a bond with anyunsubstituted carbon on the Ring A.

In some embodiments of Formula I, Ring A is selected from the groupconsisting of

wherein the carbonyl carbon of Formula I can form a bond with anyunsubstituted carbon on the Ring A.

In some embodiments of Formula I, Ring A is selected from the groupconsisting of

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R¹ is independently selected at each occurrence from the groupconsisting of H, F, Cl, Me, OMe, OH, CF₃; and CN, and n is 1 or 2.

In some embodiments, Ring A is selected from the group consisting of

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, Ring Bis phenyl.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, Ring Bis a 5-membered heteroaryl containing 1-3 heteroatoms selected from thegroup consisting of N, O, and S.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, Ring Bis a 6-membered heteroaryl containing 1-2 nitrogen atoms.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R², R^(2a), R^(2b), R^(2c), R^(2d), R^(2e), R^(2f), and/or R^(2g) is—CH₂OH.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R², R^(2a), R^(2b), R^(2c), R^(2d), R^(2e), R^(2f), and/or R^(2g) is—CH₂N(R^(3b))₂.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R², R^(2a), R^(2b), R^(2c), R^(2d), R^(2e), R^(2f), and/or R^(2b) is—CH₂NH₂.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R², R^(2a), R^(2b), R^(2c), R^(2d), R^(2e), R^(2f), and/or R^(2g) is—CH₂NHMe.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R², R^(2a), R^(2b), R^(2c), R^(2d), R^(2e), R^(2f), and/or R^(2g) is—CH₂NMe₂.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R², R^(2a), R^(2b), R^(2c), R^(2d), R^(2e), R^(2f), and/or R^(2g) is—CH₂NHEt.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R², R^(2a), R^(2b), R^(2c), R^(2d), R^(2e), R^(2f), and/or R^(2g) is—CH₂N(Me)(Et).

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R², R^(2a), R^(2b), R^(2c), R^(2d), R^(2e), R^(2f), and/or R^(2g) is—CH₂NEt₂.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, R² isindependently selected at each occurrence from the group consisting ofH, F, Cl, Me, OMe, OH, CF₃, and CN.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, R² isH.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, R² is ahalide.

In some embodiments of Formula I, Ib, Ic, Ic, If, Ih, and/or Ii, R² isF.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, R² isCl.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, R² isMe.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, R² isOH.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, R² isOMe.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, R² isCF₃.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, R² isCN.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, m is aninteger from 1-4.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, m is aninteger from 1-2.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, m is 1.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, m is 2.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, R² isF; and m is 1.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, R² isF; and m is 2.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, R² isMe; and m is 1.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, R² isMe; and m is 2.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, R² isCF₃; and m is 1.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, R² isCF₃; and m is 2.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, R² isOMe; and m is 1.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, R² isOMe; and m is 2.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, R² is Fand Me′ and m is 2.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, R² is Fand CF₃; and m is 2.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, R² is Fand OMe; and m is 2.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, R² isCN; and m is 1.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, R² isCN; and m is 2.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, R² is Fand CN; and m is 2.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, R² is—C₁₋₂ alkyl.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, R² is—C₁₋₃ alkyl.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, R² is—C₁₋₄ alkyl.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, R² is—C₁₋₅ alkyl.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, R² is—C₁₋₆ alkyl.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, R² is—C₂₋₆ alkyl.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, R² is—C₃₋₆ alkyl.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, R² is—C₄₋₆ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R³ is —C₁₋₂ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R³ is —C₁₋₃ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R³ is —C₁₋₄ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R³ is —C₁₋₅ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R³ is —C₁₋₆ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R³ and/or R^(3a) is —C₂₋₆ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R³ and/or R^(3a) is —C₃₋₆ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R³ and/or R^(3a) is —C₄₋₆ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R³ and/or R^(3a) is —C₂₋₅ alkyl.

In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/orIi, R³ and/or R^(3a) is —C₃₋₄ alkyl.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, Ring Bis a phenyl or 6-membered heteroaryl; R² is selected from the groupconsisting of F, Cl, Me, OMe, OH, CF₃, and CN; m is 1; and R² isattached to an ortho carbon of the 6-membered ring.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, Ring Bis a phenyl; R² is selected from the group consisting of F, Cl, Me, OMe,OH, CF₃; and CN; m is 1; and R² is attached to an ortho position of thephenyl ring.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, Ring Bis a pyridine; R² is selected from the group consisting of F, Cl, Me,OMe, OH, CF₃, and CN; m is 1; and R² is attached to an ortho carbon ofthe pyridine ring.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii,

is selected from the group consisting of:

wherein the carbonyl carbon of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii,can form a bond with any unsubstituted carbon on the Ring B.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii,

is selected from the group consisting of:

wherein the carbonyl carbon of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii,can form a bond with any unsubstituted carbon on the Ring B.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii,

is selected from the group consisting of:

wherein the carbonyl carbon of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii,can form a bond with any unsubstituted carbon on the Ring B.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii,

is selected from the group consisting of

and m is 1 or 2.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii,

is selected from the group consisting of

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii,

is selected from the group consisting of

and m is 1 or 2.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii,

is selected from the group consisting of

and R² is H

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii,

is selected from the group consisting of

and m is 1 or 2.

In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii,

is selected from the group consisting of

and R² is H.

Some additional embodiments of Formula I include compounds of Formula(Ia):

or salts, pharmaceutically acceptable salts, or prodrugs thereof

In some embodiments of Formula Ia, Ring A is

In some embodiments of Formula Ia, Ring B is selected from the groupconsisting of

In some embodiments of Formula Ia, each R¹ is a substituent attached toRing A and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR³, CF₃, and CN.

In some embodiments of Formula Ia, R^(2a) is a substituent attached tothe para position of phenyl and selected from the group consisting ofunsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl, Cl,Br, I, —OR^(3a), CF₃, and CN.

In some embodiments of Formula Ia, R^(2b) is a substituent attached tothe meta or ortho position of phenyl and selected from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃haloalkyl, halide, —OR^(3a), CF₃, and CN.

In some embodiments of Formula Ia, R^(2c) is 2-5 substituents, eachattached to the phenyl and are independently selected at each occurrencefrom the group consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl, halide, —OR³, CF₃, and CN.

In some embodiments of Formula Ia, R^(2d) is 1-4 substituents, eachattached to the heteroaryl ring and are independently selected at eachoccurrence from the group consisting of unsubstituted —C₁₋₆ alkyl,—CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl, halide, —OR³, CF₃, and CN.

In some embodiments of Formula Ia, R^(2e) is 1-4 substituents, eachattached to the heteroaryl ring and are independently selected at eachoccurrence from the group consisting of H, unsubstituted —C₁₋₆ alkyl,—CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl, halide, —OR³, CF₃, and CN.

In some embodiments of Formula Ia, R^(2f) is 1-3 substituents, eachattached to the heteroaryl ring and are independently selected at eachoccurrence from the group consisting of unsubstituted —C₁₋₆ alkyl,—CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl, halide, —OR³, CF₃, and CN.

In some embodiments of Formula Ia, R^(2g) is 1-3 substituents, eachattached to the heteroaryl ring and are independently selected at eachoccurrence from the group consisting of H, unsubstituted —C₁₋₆ alkyl,—CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl, halide, —OR³, CF₃, and CN.

In some embodiments of Formula Ia, each R³ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃haloalkyl, and CF₃.

In some embodiments of Formula Ia, each R^(3a) is independently selectedfrom the group consisting of unsubstituted —C₂₋₆ alkyl, —C₁₋₃ haloalkyl,and CF₃.

In some embodiments of Formula Ia, each R^(3b) is independently selectedfrom the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula Ia, each W is N or C.

In some embodiments of Formula Ia, at least two W must be N.

In some embodiments of Formula Ia, each U is N or C.

In some embodiments of Formula Ia, at least one U must be N and at leastone U must be C.

In some embodiments of Formula Ia, G is NH or O.

In some embodiments of Formula Ia, each J is N or C.

In some embodiments of Formula Ia, at least one J must be C.

In some embodiments of Formula Ia, n is an integer of 1 to 7.

In some embodiments of Formula Ia, Ring A is selected from the groupconsisting of

In some embodiments of Formula Ia, Ring B is selected from the groupconsisting of

In some embodiments of Formula Ia, Ring B is selected from the groupconsisting of

In some embodiments of Formula Ia, Ring B is selected from the groupconsisting of

In some embodiments of Formula Ia, Ring B is selected from the groupconsisting of

In some embodiments of Formula Ia, Ring B is selected from the groupconsisting of

In some embodiments of Formula Ia, Ring B is selected from the groupconsisting of

In some embodiments of Formula Ia, Ring B is selected from the groupconsisting of

In some embodiments of Formula Ia and/or Id, R^(2a) is Cl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2a) is Me.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2a) is CF₃.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2a) is CN.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2a) is 1substituent and is Me.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2a) is 2substituents and both are Me.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2a) is 1substituent and is CF₃.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2a) is 2substituents and both are CF₃.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2a) is 1substituent and is CN.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2a) is 2substituents and both are CN.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2a) is —C₁₋₂ alkyl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2a) is —C₁₋₃ alkyl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2a) is —C₁₋₄ alkyl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2a) is —C₁₋₅ alkyl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2a) is —C₁₋₆ alkyl.

In some embodiments of Formula Ia, hi, and/or Ig, R^(2a) is —C₂₋₆ alkyl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2a) is —C₃₋₆ alkyl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2a) is —C₄₋₆ alkyl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2a) is —C₂₋₅ alkyl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2a) is —C₃₋₄ alkyl.

In some embodiments of Formula Ia and/or Ig, R^(2b) is a halide.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2b) is F.

In some embodiments of Formula Ia and/or Ig, R^(2b) is Cl.

In some embodiments of Formula Ia, R^(2b) is Me.

In some embodiments of Formula Id and/or Ig, R^(2b) is OH.

In some embodiments of Formula Id and/or Ig, R^(2b) is OMe.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2b) is CF₃.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2b) is CN.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2b) is 1substituent and is F.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2b) is 2substituents and both are F.

In some embodiments of Formula Ia, R^(2b) is 1 substituent and is Me.

In some embodiments of Formula Ia, R^(2b) is 2 substituents and both areMe.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2b) is 1substituent and is CF₃.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2b) is 2substituents and both are CF₃.

In some embodiments of Formula Id and/or Ig, R^(2b) is 1 substituent andis OMe.

In some embodiments of Formula Id and/or Ig, R^(2b) is 2 substituentsand both are OMe.

In some embodiments of Formula Ia, R^(2b) is 2 substituents and are Fand Me.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2b) is 2substituents and are F and CF₃.

In some embodiments of Formula Id and/or Ig, R^(2b) is 2 substituentsand are F and OMe.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2b) is 1substituent and is CN.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2b) is 2substituents and both are CN.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2b) is 2substituents and are F and CN.

In some embodiments of Formula Ia, R^(2b) is —C₁₋₂ alkyl.

In some embodiments of Formula Ia, R^(2b) is —C₁₋₃ alkyl.

In some embodiments of Formula Ia, R^(2b) is —C₁₋₄ alkyl.

In some embodiments of Formula Ia, R^(2b) is —C₁₋₅ alkyl.

In some embodiments of Formula Ia, R^(2b) is —C₁₋₆ alkyl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2b) is —C₂₋₆ alkyl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2b) is —C₃₋₆ alkyl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2b) is —C₄₋₆ alkyl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2b) is —C₂₋₅ alkyl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2b) is —C₃₋₄ alkyl.

In some embodiments of Formula Ia and/or Ig, R^(2c) is a halide.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2c) is F.

In some embodiments of Formula Ia and/or Ig, R^(2c) is Cl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2c) is Me.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2c) is OH.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2c) is OMe.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2c) is CF₃.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2c) is CN.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2c) is 1substituent and is F.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2c) is 2substituents and both are F.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2c) is 1substituent and is Me.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2c) is 2substituents and both are Me.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2c) is 1substituent and is CF₃.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2c) is 2substituents and both are CF₃.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2c) is 1substituent and is OMe.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2c) is 2substituents and both are OMe.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2c) is 2substituents and are F and Me.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2c) is 2substituents and are F and CF₃.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2c) is 2substituents and are F and OMe.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2c) is 1substituent and is CN.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2c) is 2substituents and both are CN.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2c) is 2substituents and are F and CN.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2c) is —C₁₋₂ alkyl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2c) is —C₁₋₃ alkyl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2c) is —C₁₋₄ alkyl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2c) is —C₁₋₅ alkyl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2c) is —C₁₋₆ alkyl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2c) is —C₂₋₆ alkyl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2c) is —C₃₋₆ alkyl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2c) is —C₄₋₆ alkyl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2c) is —C₂₋₅ alkyl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2c) is —C₃₋₄ alkyl.

In some embodiments of Formula Ia and/or Ig, R^(2d) is a halide.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2d) is F.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2d) is Cl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2d) is Me.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2d) is OH.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2d) is OMe.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2d) is CF₃.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2d) is CN.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2d) is 1substituent and is F.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2d) is 2substituents and both are F.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2d) is 1substituent and is Me.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2d) is 2substituents and both are Me.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2d) is 1substituent and is CF₃.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2d) is 2substituents and both are CF₃.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2d) is 1substituent and is OMe.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2d) is 2substituents and both are OMe.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2d) is 2substituents and are F and Me.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2d) is 2substituents and are F and CF₃.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2d) is 2substituents and are F and OMe.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2d) is 1substituent and is CN.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2d) is 2substituents and both are CN.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2d) is 2substituents and are F and CN.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2d) is —C₁₋₂ alkyl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2d) is —C₁₋₃ alkyl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2d) is —C₁₋₄ alkyl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2d) is —C₁₋₅ alkyl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2d) is —C₁₋₆ alkyl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2d) is —C₂₋₆ alkyl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2d) is —C₃₋₆ alkyl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2d) is —C₄₋₆ alkyl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2d) is —C₂₋₅ alkyl.

In some embodiments of Formula Ia, Id, and/or Ig, R^(2d) is —C₃₋₄ alkyl.

In some embodiments of Formula Ia and/or Id, R^(2e) is H.

In some embodiments of Formula Ia and/or Id, R^(2e) is a halide.

In some embodiments of Formula Ia and/or Id, R^(2e) is F.

In some embodiments of Formula Ia and/or Id, R^(2e) is Cl.

In some embodiments of Formula Ia and/or Id, R^(2e) is Me.

In some embodiments of Formula Ia and/or Id, R^(2e) is OH.

In some embodiments of Formula Ia and/or Id, R^(2e) is OMe.

In some embodiments of Formula Ia and/or Id, R^(2e) is CF₃.

In some embodiments of Formula Ia and/or Id, R^(2e) is CN.

In some embodiments of Formula Ia and/or Id, R^(2e) is 1 substituent andis F.

In some embodiments of Formula Ia and/or Id, R^(2e) is 2 substituentsand both are F.

In some embodiments of Formula Ia and/or Id, R^(2e) is 1 substituent andis Me.

In some embodiments of Formula Ia and/or Id, R^(2e) is 2 substituentsand both are Me.

In some embodiments of Formula Ia and/or Id, R^(2e) is 1 substituent andis CF₃.

In some embodiments of Formula Ia and/or Id, R^(2e) is 2 substituentsand both are CF₃.

In some embodiments of Formula Ia and/or Id, R^(2e) is 1 substituent andis OMe.

In some embodiments of Formula Ia and/or Id, R^(2e) is 2 substituentsand both are OMe.

In some embodiments of Formula Ia and/or Id, R^(2e) is 2 substituentsand are F and Me.

In some embodiments of Formula Ia and/or Id, R^(2e) is 2 substituentsand are F and CF₃.

In some embodiments of Formula Ia and/or Id, R^(2e) is 2 substituentsand are F and OMe.

In some embodiments of Formula Ia and/or Id, R^(2e) is 1 substituent andis CN.

In some embodiments of Formula Ia and/or Id, R^(2e) is 2 substituentsand both are CN.

In some embodiments of Formula Ia and/or Id, R^(2e) is 2 substituentsand are F and CN.

In some embodiments of Formula Ia and/or Id, R^(2e) is —C₁₋₂ alkyl.

In some embodiments of Formula Ia and/or Id, R^(2e) is —C₁₋₃ alkyl.

In some embodiments of Formula Ia and/or Id, R^(2e) is —C₁₋₄ alkyl.

In some embodiments of Formula Ia and/or Id, R^(2e) is —C₁₋₅ alkyl.

In some embodiments of Formula Ia and/or Id, R^(2e) is —C₁₋₆ alkyl.

In some embodiments of Formula Ia and/or Id, R^(2e) is —C₂₋₆ alkyl.

In some embodiments of Formula Ia and/or Id, R^(2e) is —C₃₋₆ alkyl.

In some embodiments of Formula Ia and/or Id, R^(2e) is —C₄₋₆ alkyl.

In some embodiments of Formula Ia and/or Id, R^(2e) is —C₂₋₅ alkyl.

In some embodiments of Formula Ia and/or Id, R^(2e) is —C₃₋₄ alkyl.

In some embodiments of Formula Ia, R^(2f) is a halide.

In some embodiments of Formula Ia, R^(2f) is F.

In some embodiments of Formula Ia, R^(2f) is Cl.

In some embodiments of Formula Ia, R^(2f) is Me.

In some embodiments of Formula Ia, R^(2f) is OH.

In some embodiments of Formula Ia, R^(2f) is OMe.

In some embodiments of Formula Ia, R^(2f) is CF₃.

In some embodiments of Formula Ia, R^(2f) is CN.

In some embodiments of Formula Ia, R^(2f) is 1 substituent and is F.

In some embodiments of Formula Ia, R^(2f) is 2 substituents and both areF.

In some embodiments of Formula Ia, R^(2f) is 1 substituent and is Me.

In some embodiments of Formula Ia, R^(2f) is 2 substituents and both areMe.

In some embodiments of Formula Ia, R^(2f) is 1 substituent and is CF₃.

In some embodiments of Formula Ia, R^(2f) is 2 substituents and both areCF₃.

In some embodiments of Formula Ia, R^(2f) is 1 substituent and is OMe.

In some embodiments of Formula Ia, R^(2f) is 2 substituents and both areOMe.

In some embodiments of Formula Ia, R^(2f) is 2 substituents and are Fand Me.

In some embodiments of Formula Ia, R^(2f) is 2 substituents and are Fand CF₃.

In some embodiments of Formula Ia, R^(2f) is 2 substituents and are Fand OMe.

In some embodiments of Formula Ia, R^(2f) is 1 substituent and is CN.

In some embodiments of Formula Ia, R^(2f) is 2 substituents and both areCN.

In some embodiments of Formula Ia, R^(2f) is 2 substituents and are Fand CN.

In some embodiments of Formula Ia, R^(2f) is —C₁₋₂ alkyl.

In some embodiments of Formula Ia, R^(2f) is —C₁₋₃ alkyl.

In some embodiments of Formula Ia, R^(2f) is —C₁₋₄ alkyl.

In some embodiments of Formula Ia, R^(2f) is —C₁₋₅ alkyl.

In some embodiments of Formula Ia, R^(2f) is —C₁₋₆ alkyl.

In some embodiments of Formula Ia, R^(2f) is —C₂₋₆ alkyl.

In some embodiments of Formula Ia, R^(2f) is —C₃₋₆ alkyl.

In some embodiments of Formula Ia, R^(2f) is —C₄₋₆ alkyl.

In some embodiments of Formula Ia, R^(2f) is —C₂₋₅ alkyl.

In some embodiments of Formula Ia, R^(2f) is —C₃₋₄ alkyl.

In some embodiments of Formula Ia, R^(2g) is H.

In some embodiments of Formula Ia, R^(2g) is a halide.

In some embodiments of Formula Ia, R^(2g) is F.

In some embodiments of Formula Ia, R^(2g) is Cl.

In some embodiments of Formula Ia, R^(2g) is Me.

In some embodiments of Formula Ia, R^(2g) is OH.

In some embodiments of Formula Ia, R^(2g) is OMe.

In some embodiments of Formula Ia, R^(2g) is CF₃.

In some embodiments of Formula Ia, R^(2g) is CN.

In some embodiments of Formula Ia, R^(2g) is 1 substituent and is F.

In some embodiments of Formula Ia, R^(2g) is 2 substituents and both areF.

In some embodiments of Formula Ia, R^(2g) is 1 substituent and is Me.

In some embodiments of Formula Ia, R^(2g) is 2 substituents and both areMe.

In some embodiments of Formula Ia, R^(2g) is 1 substituent and is CF₃.

In some embodiments of Formula Ia, R^(2g) is 2 substituents and both areCF₃.

In some embodiments of Formula Ia, R^(2g) is 1 substituent and is OMe.

In some embodiments of Formula Ia, R^(2g) is 2 substituents and both areOMe.

In some embodiments of Formula Ia, R^(2g) is 2 substituents and are Fand Me.

In some embodiments of Formula Ia, R^(2g) is 2 substituents and are Fand CF₃.

In some embodiments of Formula Ia, R^(2g) is 2 substituents and are Fand OMe.

In some embodiments of Formula Ia, R^(2g) is 1 substituent and is CN.

In some embodiments of Formula Ia, R^(2g) is 2 substituents and both areCN.

In some embodiments of Formula Ia, R^(2g) is 2 substituents and are Fand CN.

In some embodiments of Formula Ia, R^(2g) is —C₁₋₂ alkyl.

In some embodiments of Formula Ia, R^(2g) is —C₁₋₃ alkyl.

In some embodiments of Formula Ia, R^(2g) is —C₁₋₄ alkyl.

In some embodiments of Formula Ia, R^(2g) is —C₁₋₅ alkyl.

In some embodiments of Formula Ia, R^(2g) is —C₁₋₆ alkyl.

In some embodiments of Formula Ia, R^(2g) is —C₂₋₆ alkyl.

In some embodiments of Formula Ia, R^(2g) is —C₃₋₆ alkyl.

In some embodiments of Formula Ia, R^(2g) is —C₄₋₆ alkyl.

In some embodiments of Formula Ia, R^(2g) is —C₂₋₅ alkyl.

In some embodiments of Formula Ia, R^(2g) is —C₃₋₄ alkyl.

Some additional embodiments of Formula I include compounds of Formula(Ib):

or salts, pharmaceutically acceptable salts, or prodrugs thereof.

In some embodiments of Formula Ib, Ring A is

In some embodiments of Formula Ib, Ring B is selected from the groupconsisting of phenyl and a 5-6 membered heteroaryl, wherein a carbonatom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula Ib, each R¹ is a substituent attached toRing A and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR³, CF₃, and CN.

In some embodiments of Formula Ib, each R² is a substituent attached toRing B and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂,—C₁₋₃ haloalkyl, halide, —OR³, CF₃, and CN.

In some embodiments of Formula Ib, each R³ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃haloalkyl, and CF₃.

In some embodiments of Formula Ib, each R^(3b) is independently selectedfrom the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula Ib, each M is independently selected fromthe group consisting of N, C, S and O.

In some embodiments of Formula Ib, both M are not O.

In some embodiments of Formula Ib, both M are not C.

In some embodiments of Formula Ib, m is an integer of 1 to 5.

In some embodiments of Formula Ib, n is an integer of 1 to 10.

In some embodiments of Formula Ib, Ring A is selected from the groupconsisting of

Some additional embodiments of Formula I include compounds of Formula(Ic):

or salts, pharmaceutically acceptable salts, or prodrugs thereof.

In some embodiments of Formula Ic, Ring A is

In some embodiments of Formula Ic, Ring B is selected from the groupconsisting of phenyl and a 5-6 membered heteroaryl, wherein a carbonatom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula Ic, each R¹ is a substituent attached toRing A and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR³, CF₃, and CN.

In some embodiments of Formula Ic, each R² is a substituent attached toRing B and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂,—C₁₋₃ haloalkyl, halide, —OR³, CF₃, and CN.

In some embodiments of Formula Ic, each R³ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃haloalkyl, and CF₃.

In some embodiments of Formula Ic, each R^(3b) is independently selectedfrom the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula Ic, each M is independently selected fromthe group consisting of N, C, S and O.

In some embodiments of Formula Ic, if one M is C, the other M isselected from the group consisting of N, S, and O.

In some embodiments of Formula Ic, m is an integer of 1 to 5.

In some embodiments of Formula Ic, n is an integer of 1 to 10.

In some embodiments of Formula Ic, Ring A is selected from the groupconsisting of

Some additional embodiments of Formula I include compounds of Formula(Id):

or salts, pharmaceutically acceptable salts, or prodrugs thereof.

In some embodiments of Formula Id, Ring A is

In some embodiments of Formula Id, Ring B is selected from the groupconsisting of

and a 5-6 membered heteroarylR^(2e), wherein a carbon atom on the ringis attached to the carbonyl carbon.

In some embodiments of Formula Id, each R¹ is a substituent attached toRing A and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR³, CF₃, and CN.

In some embodiments of Formula Id, R^(2a) is a substituent attached tothe para position of phenyl and selected from the group consisting of H,unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl, Cl,Br, I, —OR^(3a), CF₃, and CN.

In some embodiments of Formula hl, R^(2b) is a substituent attached tothe meta position of phenyl and selected from the group consisting of H,unsubstituted —C₂₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl, F,I, —OR³, CF₃, and CN.

In some embodiments of Formula Id, R^(2e) is a substituent attached tothe ortho position of phenyl and selected from the group consisting ofH, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl,F, Br, I, —OR³, CF₃, and CN.

In some embodiments of Formula Id, R^(2d) is 2-5 substituents, eachattached to the phenyl and are independently selected at each occurrencefrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl, halide, —OR³, CF₃, and CN.

In some embodiments of Formula Id, R^(2e) is 1-3 substituents, eachattached to the heteroaryl ring and are independently selected at eachoccurrence from the group consisting of H, unsubstituted —C₁₋₆ alkyl,—CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl, halide, —OR³, CF₃, and CN.

In some embodiments of Formula Id, each R³ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃haloalkyl, and CF₃.

In some embodiments of Formula Id, each R^(3a) is independently selectedfrom the group consisting of H, unsubstituted —C₂₋₆ alkyl, —C₁₋₃haloalkyl, and CF₃;

In some embodiments of Formula Id, each R^(3b) is independently selectedfrom the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula Id, Q is S or NH.

In some embodiments of Formula Id, n is an integer of 1 to 5.

In some embodiments of Formula Id, Ring A is selected from the groupconsisting of

In some embodiments of Formula Id, R^(2a) is H.

In some embodiments of Formula Id, R^(2b) is H.

In some embodiments of Formula Id, R^(2c) is H.

In some embodiments of Formula Id, R^(2d) is H.

Some additional embodiments of Formula I include compounds of Formula(Ie):

or salts, pharmaceutically acceptable salts, or prodrugs thereof.

In some embodiments of Formula Ie, Ring A is

In some embodiments of Formula Ie, Ring B is selected from the groupconsisting of phenyl and a 5-6 membered heteroaryl, wherein a carbonatom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula Ie, each R¹ is a substituent attached toRing A and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR³, CF₃, and CN.

In some embodiments of Formula Ie, each R² is a substituent attached toRing B and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂,—C₁₋₃ haloalkyl, halide, —OR³, CF₃, and CN.

In some embodiments of Formula Ie, each R³ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃haloalkyl, and CF₃.

In some embodiments of Formula Ie, each R^(3b) is independently selectedfrom the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula Ie, each W is N or C.

In some embodiments of Formula Ie, at least one W must be N.

In some embodiments of Formula Ie, Q is S or NH.

In some embodiments of Formula Ie, m is an integer of 1 to 5.

In some embodiments of Formula Ie, n is an integer of 1 to 4.

In some embodiments of Formula Ie, Ring A is selected from the groupconsisting of

Some additional embodiments of Formula I include compounds of Formula(If):

or salts, pharmaceutically acceptable salts, or prodrugs thereof.

In some embodiments of Formula If, Ring A is

In some embodiments of Formula If, Ring B is selected from the groupconsisting of phenyl and a 5-6 membered heteroaryl, wherein a carbonatom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula If, each R¹ is a substituent attached toRing A and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR³, CF₃, and CN.

In some embodiments of Formula If, each R² is a substituent attached toRing B and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂,—C₁₋₃ haloalkyl, halide, —OR³, CF₃, and CN.

In some embodiments of Formula If, each R³ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃haloalkyl, and CF₃.

In some embodiments of Formula If, each R^(3b) is independently selectedfrom the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula If, each W is N or C.

In some embodiments of Formula If, m is an integer of 1 to 5.

In some embodiments of Formula If, n is an integer of 1 to 5.

In some embodiments of Formula If, Ring A is selected from the groupconsisting of

Some additional embodiments of Formula I include compounds of Formula(Ig):

or salts, pharmaceutically acceptable salts, or prodrugs thereof.

In some embodiments of Formula Ig, Ring A is

In some embodiments of Formula Ig, Ring B is selected from the groupconsisting of

and a 5-6 membered heteroarylR^(2d), wherein a carbon atom on the ringis attached to the carbonyl carbon.

In some embodiments of Formula Ig, each R¹ is a substituent attached toRing A and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR³, CF₃, and CN.

In some embodiments of Formula Ig, R^(2a) is a substituent attached tothe para position of phenyl and is selected from the group consisting ofunsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl, F,I, —OR³, CF₃, and CN.

In some embodiments of Formula Ig, R^(2b) is a substituent attached tothe meta or ortho position of phenyl and is selected from the groupconsisting of unsubstituted —C₂₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃haloalkyl, halide, —OR³, CF₃, and CN.

In some embodiments of Formula Ig, R^(2c) is 2-5 substituents, eachattached to the phenyl and are independently selected at each occurrencefrom the group consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl, halide, —OR³, CF₃, and CN.

In some embodiments of Formula Ig, R^(2d) is 1-3 substituents, eachattached to the heteroaryl ring and are independently selected at eachoccurrence from the group consisting of H, unsubstituted —C₁₋₆ alkyl,—CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl, halide, —OR³, CF₃, and CN.

In some embodiments of Formula Ig, each R³ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃haloalkyl, and CF₃.

In some embodiments of Formula Ig, each R^(3b) is independently selectedfrom the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula Ig, Q is independently selected from thegroup consisting of O, S, and NH.

In some embodiments of Formula Ig, n is an integer of 1 to 5.

In some embodiments of Formula Ig, Ring A is selected from the groupconsisting of

In some embodiments of Formula Ig, R^(2a) is F.

In some embodiments of Formula Ig, R^(2a) is OH.

In some embodiments of Formula Ig, R^(2a) is OMe.

In some embodiments of Formula Ig, R^(2a) is 1 substituent and is F.

In some embodiments of Formula Ig, R^(2a) is 2 substituents and both areF.

In some embodiments of Formula Ig, R^(2a) is 1 substituent and is OMe.

In some embodiments of Formula Ig, R^(2a) is 2 substituents and both areOMe.

In some embodiments of Formula Ig, R^(2a) is 2 substituents and are Fand Me.

In some embodiments of Formula Ig, R^(2a) is 2 substituents and are Fand CF₃.

In some embodiments of Formula Ig, R^(2a) is 2 substituents and are Fand OMe.

In some embodiments of Formula Ig, R^(2a) is 2 substituents and are Fand CN.

Some additional embodiments of Formula I include compounds of Formula(Ih):

or salts, pharmaceutically acceptable salts, or prodrugs thereof.

In some embodiments of Formula Ih, Ring A is

In some embodiments of Formula Ih, Ring B is selected from the groupconsisting of phenyl and a 5-6 membered heteroaryl, wherein a carbonatom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula Ih, each R¹ is a substituent attached toRing A and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR³, CF₃, and CN.

In some embodiments of Formula Ih, each R² is a substituent attached toRing B and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂,—C₁₋₃ haloalkyl, halide, —OR³, CF₃, and CN.

In some embodiments of Formula Ih, each R³ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃haloalkyl, and CF₃.

In some embodiments of Formula Ih, each R^(3b) is independently selectedfrom the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula Ih, each W is N or C.

In some embodiments of Formula Ih, at least one W must be N.

In some embodiments of Formula Ih, Q is independently selected from thegroup consisting of O, S, and NH.

In some embodiments of Formula Ih, m is an integer of 1 to 5.

In some embodiments of Formula Ih, n is an integer of 1 to 4.

In some embodiments of Formula Ih, Ring A is selected from the groupconsisting of

Some additional embodiments of Formula I include compounds of Formula(Ii):

or salts, pharmaceutically acceptable salts, or prodrugs thereof.

In some embodiments of Formula Ii, Ring A is

wherein a carbon atom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula Ii, Ring B is selected from the groupconsisting of phenyl and a 5-6 membered heteroaryl, wherein a carbonatom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula Ii, each R¹ is a substituent attached toRing A and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR³, CF₃, and CN.

In some embodiments of Formula Ii, each R² is a substituent attached toRing B and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂,—C₁₋₃ haloalkyl, halide, —OR³, CF₃, and CN.

In some embodiments of Formula Ii, each R³ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃haloalkyl, and CF₃.

In some embodiments of Formula Ii, each R^(3b) is independently selectedfrom the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula Ii, each W is N or C.

In some embodiments of Formula Ii, at least one W is C

In some embodiments of Formula Ii, Q is independently selected from thegroup consisting of O, S, and N.

In some embodiments of Formula Ii, m is an integer of 1 to 5.

In some embodiments of Formula Ii, n is an integer of 1 to 7.

In some embodiments of Formula Ii, Ring A is selected from the groupconsisting of

Some embodiments of the present disclosure include compounds of Formula(II):

or salts, pharmaceutically acceptable salts, or prodrugs thereof.

In some embodiments of Formula II, Ring C is a 5-6 membered heteroaryl,wherein a carbon atom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula II, Ring D is selected from the groupconsisting of phenyl and a 5-6 membered heteroaryl, wherein a carbonatom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula II, each R⁴ is a substituent attached toRing C and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR⁶, CF₃, and CN.

In some embodiments of Formula II, each R⁵ is a substituent attached toRing D and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂,—C₁₋₃ haloalkyl, halide, —OR⁶, CF₃, and CN.

In some embodiments of Formula II, each R⁶ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃haloalkyl, and CF₃.

In some embodiments of Formula II, each R^(6b) is independently selectedfrom the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula II, each q is an integer of 1 to 4.

In some embodiments of Formula II, each p is an integer of 1 to 5.

In some embodiments of Formula II, there is the proviso that a compoundof Formula II is not a compound selected from the group consisting of:

In some embodiments of Formula II, Ring C is a 5-membered heteroarylring containing 1-3 heteroatoms selected from the group consisting of N,O, and S.

In some embodiments of Formula II,

is selected from the group consisting of

and p is 1 or 2.

In some embodiments of Formula II,

In some embodiments of Formula II, Ring C is a 6-membered heteroarylring containing 1-2 nitrogens.

In some embodiments of Formula II,

is selected from the group consisting of

and p is 1 or 2.

In some embodiments of Formula II,

In some embodiments of Formula II, each R⁴ is independently selectedfrom the group consisting of H, F, Cl, Me, OMe, OH, CF₃ and CN.

In some embodiments of Formula II, IIa, IIc, IId, IIe, and/or IIf, eachR⁴ is independently selected from the group consisting of H, F, Cl, Me,OMe, OH, CF₃ and CN; and p is 1 or 2.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁴ is H.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁴ is a halide.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or R⁴ isF.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁴ is Cl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁴ is Me.

In some embodiments of Formula II, IIa, IIc, IId, IIe, and/or IIf, R⁴ isOH.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁴ is OMe.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁴ is CF₃.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁴ is CN.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,p is an integer from 1-3.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,p is an integer from 1-2.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,p is 2.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,p is 1.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁴ is F; and p is 1.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁴ is F; and p is 2.

In some embodiments of Formula II, IIa, IIc, IId, IIe, and/or IIf, R⁴ isOH; and p is 1.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁴ is OMe; and p is an integer from 1-2.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁴ is —C₁₋₂ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁴ is —C₁₋₃ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁴ is —C₁₋₄ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁴ is —C₁₋₅ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁴ is —C₁₋₆ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁴ is —C₂₋₆ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁴ is —C₃₋₆ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁴ is —C₄₋₆ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁴ is —C₂₋₅ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁴ is —C₃₋₅ alkyl.

In some embodiments of Formula II, Ring C is selected from the groupconsisting of:

In some embodiments of Formula II and/or IIb, Ring D is phenyl.

In some embodiments of Formula II and/or IIb,

is selected from the group consisting of

and q is 1 or 2.

In some embodiments of Formula II and/or IIb,

is selected from the group consisting of

In some embodiments of Formula II and/or III), Ring D is a 5-memberedheteroaryl containing 1-3 heteroatoms selected from the group consistingof N, O, and S.

In some embodiments of Formula II and/or IIb,

is selected from the group consisting of

and q is 1 or 2.

In some embodiments of Formula II and/or IIb,

is selected from the group consisting of

In some embodiments of Formula II and/or IIb, Ring D is a 6-memberedheteroaryl containing 1-2 nitrogen atoms.

In some embodiments of Formula II and/or IIb,

is selected from the group consisting of

and q is 1 or 2.

In some embodiments of Formula II and/or IIb,

is selected from the group consisting of

and R⁵ is H.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁵, R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R^(5h),and/or R^(5i) is —CH₂OH.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁵, R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R^(5h),and/or R^(5i) is —CH₂N(R^(3b))₂.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁵, R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R^(5h), and/or R^(5i) is—CH₂NH₂.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁵, R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R^(5h),and/or R^(5i) is —CH₂NHMe.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁵, R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R^(5h),and/or R^(5i) is —CH₂NMe₂.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁵, R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R^(5h),and/or R^(5i) is —CH₂NHEt.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁵, R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R^(5h),and/or R^(5i) is —CH₂N(Me)(Et).

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁵, R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R^(5h),and/or R^(5i) is —CH₂NEt₂.

In some embodiments of Formula II and/or IIb, each R⁵ is independentlyselected from the group consisting of H, F, Cl, Me, OMe, OH, CF₃, andCN.

In some embodiments of Formula II and/or IIb, R⁵ is H.

In some embodiments of Formula II and/or IIb, R⁵ is a halide.

In some embodiments of Formula II and/or IIb, R⁵ is F.

In some embodiments of Formula II and/or IIb, R³ is Cl.

In some embodiments of Formula II and/or IIb, R⁵ is Me.

In some embodiments of Formula II and/or IIb, R⁵ is OH.

In some embodiments of Formula II and/or IIb, R⁵ is OMe.

In some embodiments of Formula II and/or IIb, R⁵ is CF₃.

In some embodiments of Formula II and/or IIb, R⁵ is CN.

In some embodiments of Formula II and/or IIb, q is an integer from 1-4.

In some embodiments of Formula II and/or IIb, q is an integer from 1-2.

In some embodiments of Formula II and/or IIb, q is 1.

In some embodiments of Formula II and/or IIb, q is 2.

In some embodiments of Formula II and/or IIb, R⁵ is F; and q is 1.

In some embodiments of Formula II and/or IIb, R⁵ is F; and q is 2.

In some embodiments of Formula II and/or IIb, R⁵ is Me; and q is 1.

In some embodiments of Formula II and/or IIb, R⁵ is Me; and q is 2.

In some embodiments of Formula II and/or IIb, R⁵ is CF₃; and q is 1.

In some embodiments of Formula II and/or IIb, R⁵ is CF₃; and q is 2.

In some embodiments of Formula II and/or IIb, R⁵ is OMe; and q is 1.

In some embodiments of Formula II and/or IIb, R⁵ is OMe; and q is 2.

In some embodiments of Formula II and/or IIb, R⁵ is F and Me; and q is2.

In some embodiments of Formula II and/or IIb, R⁵ is F and CF₃; and q is2.

In some embodiments of Formula II and/or IIb, R⁵ is F and OMe; and q is2.

In some embodiments of Formula II and/or IIb, R⁵ is CN; and q is 1.

In some embodiments of Formula II and/or IIb, R⁵ is CN; and q is 2.

In some embodiments of Formula II and/or IIb, R⁵ is F and CN; and q is2.

In some embodiments of Formula II and/or IIb, R⁵ is —C₁₋₂ alkyl.

In some embodiments of Formula II and/or IIb, R⁵ is —C₁₋₃ alkyl.

In some embodiments of Formula II and/or IIb, R⁵ is —C₁₋₄ alkyl.

In some embodiments of Formula II and/or IIb, R⁵ is —C₁₋₅ alkyl.

In some embodiments of Formula II and/or IIb, R⁵ is —C₁₋₆ alkyl.

In some embodiments of Formula II and/or IIb, R⁵ is —C₂₋₆ alkyl.

In some embodiments of Formula II and/or IIb, R⁵ is —C₃₋₆ alkyl.

In some embodiments of Formula II and/or IIb, R⁵ is —C₄₋₆ alkyl.

In some embodiments of Formula II and/or IIb, R⁵ is —C₂₋₅ alkyl.

In some embodiments of Formula II and/or IIb, R⁵ is —C₃₋₅ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁶ is —C₁₋₂ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁶ is —C₁₋₃ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁶ is —C₁₋₄ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁶ is —C₁₋₅ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁶ is —C₁₋₆ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁶ is —C₂₋₆ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁶ is —C₃₋₆ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁶ is —C₄₋₆ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁶ is —C₂₋₅ alkyl.

In some embodiments of Formula II, IIa, IIb, IIc, IId, IIe, and/or IIf,R⁶ is —C₃₋₅ alkyl.

In some embodiments of Formula II, Ring D is a phenyl or 6-memberedheteroaryl; R⁵ is selected from the group consisting of F, Cl, Me, OMe,OH, CF₃ and CN; q is 1; and R⁵ is attached to an ortho carbon of the6-membered ring.

In some embodiments of Formula II, Ring D is a phenyl, R⁵ is selectedfrom the group consisting of F, Cl, Me, OMe, OH, CF₃ and CN; q is 1; andR⁵ is attached to an ortho position of the phenyl ring.

In some embodiments of Formula II, Ring D is a pyridine, R⁵ is selectedfrom the group consisting of F, Cl, Me, OMe, OH, CF₃ and CN; q is 1; andR⁵ is attached to an ortho carbon of the pyridine ring.

In some embodiments of Formula II,

is selected from the group consisting of:

wherein the carbonyl carbon of Formula II can form a bond with anyunsubstituted carbon on the Ring D.

In some embodiments of Formula II,

is selected from the group consisting of:

wherein the carbonyl carbon of Formula II can form a bond with anyunsubstituted carbon on the Ring D.

In some embodiments of Formula II,

is selected from the group consisting of:

wherein the carbonyl carbon of Formula II can form a bond with anyunsubstituted carbon on the Ring D.

Some additional embodiments of Formula II include compounds of Formula(IIa):

or salts, pharmaceutically acceptable salts, or prodrugs thereof.

In some embodiments of Formula IIa, Ring C is

In some embodiments of Formula IIa, Ring D is selected from the groupconsisting of

wherein a carbon atom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula IIa, each R⁴ is a substituent attached toRing C and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR⁶, CF₃, and CN.

In some embodiments of Formula IIa, R^(5a) is 1-5 substituents, eachattached to Ring D and are independently selected at each occurrencefrom the group consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(6b))₂, —C₁₋₃ haloalkyl, halide, —OR^(6a), CF₃, and CN.

In some embodiments of Formula IIa, R^(5b) is 1-4 substituents, eachattached to Ring D and are independently selected at each occurrencefrom the group consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(6b))₂, haloalkyl, F, I, —OR^(6a), CF₃, and CN.

In some embodiments of Formula IIa, R^(5c) is 1-3 substituents, eachattached to Ring D and are independently selected at each occurrencefrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(6b))₂, —C₁₋₃ haloalkyl, halide, —OR⁶, CF₃, and CN.

In some embodiments of Formula IIa, R^(5d) is 1-2 substituents, eachattached to Ring D and are independently selected at each occurrencefrom the group consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R)₂, —C₁₋₃ haloalkyl, halide, —OR⁶, CF₃, and CN.

In some embodiments of Formula IIa, R^(5e) is 1-3 substituents, eachattached to Ring D and are independently selected at each occurrencefrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(6b))₂, —C₁₋₃ haloalkyl, halide, —OR⁶, CF₃, and CN.

In some embodiments of Formula IIa, each R⁶ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃haloalkyl, and CF₃.

In some embodiments of Formula IIa, each R^(6a) is independentlyselected from the group consisting of H, unsubstituted —C₂₋₆ alkyl,—C₁₋₃ haloalkyl, and CF₃.

In some embodiments of Formula IIa, each R^(6b) is independentlyselected from the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula IIa, each A is N or C.

In some embodiments of Formula IIa, at least two A must be N.

In some embodiments of Formula IIa, each J is N or C.

In some embodiments of Formula IIa, at least one J must be N and atleast one J must be C.

In some embodiments of Formula IIa, each U is N or C.

In some embodiments of Formula IIa, at least one U must be C.

In some embodiments of Formula IIa, Q is O or N.

In some embodiments of Formula IIa, p is an integer of 1 to 4.

In some embodiments of Formula IIa, Ring D is selected from the groupconsisting of

wherein a carbon atom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula IIa, Ring D is selected from the groupconsisting of:

In some embodiments of Formula IIa, IId, IIe, and/or IIf, R^(5a) is 1substituent and is F.

In some embodiments of Formula IIa, IId, IIe, and/or IIf, R^(5a) is 2substituents and are both F.

In some embodiments of Formula IIa, IIe, and/or IIf, R^(5a) is 1substituent and is Me.

In some embodiments of Formula IIa, IIe, and/or IIf, R^(5a) is 2substituents and are both Me.

In some embodiments of Formula IIa, IId, IIe, and/or IIf, R^(5a) is 1substituent and is CF₃.

In some embodiments of Formula IIa, IId, IIe, and/or IIf, R^(5a) is 2substituents and are both CF₃.

In some embodiments of Formula IIa, IIe, and/or III, R^(5a) is 2substituents and are F and Me.

In some embodiments of Formula IIa, IId, IIe, and/or IIf, R^(5a) is 2substituents and are F and CF₃.

In some embodiments of Formula IIa, IIc, IId, IIe, and/or IIf, R^(5a) is1 substituent and is CN.

In some embodiments of Formula IIa, IIc, IId, IIe, and/or IIf, R^(5a) is2 substituents and are both CN.

In some embodiments of Formula IIa, IId, IIe, and/or IIf, R^(5a) is 2substituents and are F and CN.

In some embodiments of Formula IIa, IIe, and/or IIf, R^(5a) is —C₁₋₂alkyl.

In some embodiments of Formula IIa, IIe, and/or IIf, R^(5a) is —C₁₋₃alkyl.

In some embodiments of Formula IIa, IIe, and/or IIf, R^(5a) is —C₁₋₄alkyl.

In some embodiments of Formula IIa, IIe, and/or IIf, R^(5a) is —C₁₋₅alkyl.

In some embodiments of Formula IIa, IIe, and/or IIf, R^(5a) is —C₁₋₆alkyl.

In some embodiments of Formula IIa, IId, IIe, and/or IIf, R^(5a) is—C₂₋₆ alkyl.

In some embodiments of Formula IIa, IId, IIe, and/or IIf, R^(5a) is—C₃₋₆ alkyl.

In some embodiments of Formula IIa, IId, IIe, and/or IIf, R^(5a) is—C₄₋₆ alkyl.

In some embodiments of Formula IIa, IId, IIe, and/or IIf, R^(5a) is—C₂₋₅ alkyl.

In some embodiments of Formula IIa, IId, IIe, and/or IIf, R^(5a) is—C₃₋₅ alkyl.

In some embodiments of Formula IIa, IIc, IId, IIe, and/or IIf, R^(5b) is1 substituent and is F.

In some embodiments of Formula IIa, IIc, IId, IIe, and/or IIf, R^(5b) is2 substituents and both are F.

In some embodiments of Formula IIa, IIc, IId, IIe, and/or IIf, R^(5b) is1 substituent and is Me.

In some embodiments of Formula IIa, IIc, IId, IIe, and/or IIf, R^(5b) is2 substituents and both are Me.

In some embodiments of Formula IIa, IId, IIe, and/or IIf, R^(5b) is 1substituent and is CF₃.

In some embodiments of Formula IIa, IId, IIe, and/or IIf, R^(5b) is 2substituents and both are CF₃.

In some embodiments of Formula IIa, IIc, IId, IIe, and/or IIf, R^(5b) is2 substituents and are F and Me.

In some embodiments of Formula IIa, IId, IIe, and/or IIf, R^(5b) is 2substituents and are F and CF₃.

In some embodiments of Formula IIa, IIc, IId, IIe, and/or IIf, R^(5b) is1 substituent and is CN.

In some embodiments of Formula IIa, IIc, IId, IIe, and/or IIf, R^(5b) is2 substituents and both are CN.

In some embodiments of Formula IIa, IIc, IId, IIe, and/or IIf, R^(5b) is2 substituents and are F and CN.

In some embodiments of Formula IIa, IIc, IId, IIe, and/or IIf, R^(5b) is—C₁₋₂ alkyl.

In some embodiments of Formula IIa, IIc, IId, IIe, and/or IIf, R^(5b) is—C₁₋₃ alkyl.

In some embodiments of Formula IIa, IIc, IId, IIe, and/or IIf, R^(5b) is—C₁₋₄ alkyl.

In some embodiments of Formula IIa, IIc, IId, IIe, and/or IIf, R^(5b) is—C₁₋₅ alkyl.

In some embodiments of Formula IIa, IIc, IId, IIe, and/or IIf, R^(5b) is—C₁₋₆ alkyl.

In some embodiments of Formula IIa, IIc, IId, IIe, and/or IIf, R^(5b) is—C₂₋₆ alkyl.

In some embodiments of Formula IIa, IIc, IId, IIe, and/or IIf, R^(5b) is—C₃₋₆ alkyl.

In some embodiments of Formula IIa, IIc, IId, IIe, and/or IIf, R^(5b) is—C₄₋₆ alkyl.

In some embodiments of Formula IIa, IIc, IId, IIe, and/or IIf, R^(5b) is—C₂₋₅ alkyl.

In some embodiments of Formula IIa, IIc, IId, IIe, and/or IIf, R^(5b) is—C₃₋₅ alkyl.

In some embodiments of Formula IIa and/or IIb, R^(5c) is H.

In some embodiments of Formula IIa, IId, and/or IIe, R^(5c) is a halide.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5c) is F.

In some embodiments of Formula IIa, IId, and/or IIe, R^(5c) is Cl.

In some embodiments of Formula IIa and/or IIc, R^(5c) is Me.

In some embodiments of Formula IIa, IId, and/or IIe, R^(5c) is OH.

In some embodiments of Formula IIa, IId, and/or IIe, R^(5c) is OMe.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5c) is CF₃.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5c) is CN.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5c) is 1substituent and is F.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5c) is 2substituents and are both F.

In some embodiments of Formula IIa and/or IIc, R^(5c) is 1 substituentand is Me.

In some embodiments of Formula IIa and/or IIc, R^(5c) is 2 substituentsand are both Me.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5c) is 1substituent and is CF₃.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5c) is 2substituents and both are CF₃.

In some embodiments of Formula IIa, IId, and/or IIe, R^(5c) is 1substituent and is OMe.

In some embodiments of Formula IIa, IId, and/or IIe, R^(5c) is 2substituents and both are OMe.

In some embodiments of Formula IIa and/or IIe, R^(5c) is 2 substituentsand are F and Me.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5c) is 2substituents and are F and CF₃.

In some embodiments of Formula IIa, IId, and/or IIe, R^(5c) is 2substituents and are F and OMe.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5c) is 1substituent and is CN.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5c) is 2substituents and both are CN.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5c) is 2substituents and are F and CN.

In some embodiments of Formula IIa and/or IIe, R^(5c) is —C₁₋₂ alkyl.

In some embodiments of Formula IIa and/or IIc, R^(5c) is —C₁₋₃ alkyl.

In some embodiments of Formula IIa and/or IIe, R^(5c) is —C₁₋₄ alkyl.

In some embodiments of Formula IIa and/or IIc, R^(5a) is —C₁₋₅ alkyl.

In some embodiments of Formula IIa and/or IIe, R^(5a) is —C₁₋₆ alkyl.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5c) is—C₂₋₆ alkyl.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5c) is—C₃₋₆ alkyl.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5e) is—C₄₋₆ alkyl.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5c) is—C₂₋₅ alkyl.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5c) is—C₃₋₅ alkyl.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5d) is ahalide.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5d) is F.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5d) is Cl.

In some embodiments of Formula IIa, IIc, and/or IId, R^(5d) is Me.

In some embodiments of Formula IIa, and/or IId, R^(5d) is OH.

In some embodiments of Formula IIa, and/or IId, R^(5d) is OMe.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5d) is CF₃.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5d) is CN.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5d) is 1substituent and is F.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5d) is 2substituents and both are F.

In some embodiments of Formula IIa, IIe, and/or IId, R^(5d) is 1substituent and is Me.

In some embodiments of Formula IIa, IIe, and/or IId, R^(5d) is 2substituents and both are Me.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5d) is 1substituent and is CF₃.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5d) is 2substituents and both are CF₃.

In some embodiments of Formula IIa and/or IId, R^(5d) is 1 substituentand is OMe.

In some embodiments of Formula IIa and/or IId, R^(5d) is 2 substituentsand are both OMe.

In some embodiments of Formula IIa, IIc, and/or IId, R^(5d) is 2substituents and are F and Me.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5d) is 2substituents and are F and CF₃.

In some embodiments of Formula IIa and/or IId, R^(5d) is 2 substituentsand are F and OMe.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5d) is 1substituent and is CN.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5d) is 2substituents and both are CN.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5d) is 2substituents and are F and CN.

In some embodiments of Formula IIa, IIe, and/or IId, R^(5d) is —C₁₋₂alkyl.

In some embodiments of Formula IIa, IIe, and/or IId, R^(5d) is —C₁₋₃alkyl.

In some embodiments of Formula IIa, IIe, and/or IId, R^(5d) is —C₁₋₄alkyl.

In some embodiments of Formula IIa, IIe, and/or IId, R^(5d) is —C₁₋₅alkyl.

In some embodiments of Formula IIa, IIe, and/or IId, R^(5d) is —C₁₋₆alkyl.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5d) is—C₂₋₆ alkyl.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5d) is—C₃₋₆ alkyl.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5d) is—C₄₋₆ alkyl.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5d) is—C₂₋₅ alkyl.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5d) is—C₃₋₅ alkyl.

In some embodiments of Formula IIa and/or IId, R^(5e) is H.

In some embodiments of Formula IIa and/or IId, R^(5e) is a halide.

In some embodiments of Formula IIa, IIe, and/or IId, R^(5e) is F.

In some embodiments of Formula IIa and/or IId, R^(5e) is Cl.

In some embodiments of Formula IIa and/or IId, R^(5e) is Me.

In some embodiments of Formula IIa, IIe, and/or IId, R^(5e) is OH.

In some embodiments of Formula IIa, IIe, and/or IId, R^(5e) is OMe.

In some embodiments of Formula IIa and/or IId, R^(5e) is CF₃.

In some embodiments of Formula IIa, IIe, and/or IId, R^(5e) is CN.

In some embodiments of Formula IIa, IIc, and/or IId, R^(5e) is 1substituent and is F.

In some embodiments of Formula IIa, IIe, and/or IId, R^(5e) is 2substituents and are both F.

In some embodiments of Formula IIa and/or IId, R^(5e) is 1 substituentand is Me.

In some embodiments of Formula IIa and/or IId, R^(5e) is 2 substituentsand are both Me.

In some embodiments of Formula IIa and/or IId, R^(5e) is 1 substituentand is CF₃.

In some embodiments of Formula IIa and/or IId, R^(5e) is 2 substituentsand are both CF₃.

In some embodiments of Formula IIa, IIc, and/or IId, R^(5e) is 1substituent and is OMe.

In some embodiments of Formula IIa, IIe, and/or IId, R^(5e) is 2substituents and are both OMe.

In some embodiments of Formula IIa and/or IId, R^(5e) is 2 substituentsand are F and Me.

In some embodiments of Formula IIa and/or IId, R^(5e) is 2 substituentsand are F and CF₃.

In some embodiments of Formula IIa, IIe, and/or IId, R^(5e) is 2substituents and are F and OMe.

In some embodiments of Formula IIa, IIc, and/or IId, R^(5e) is 1substituent and is CN.

In some embodiments of Formula IIa, IIc, and/or IId, R^(5e) is 2substituents and are both CN.

In some embodiments of Formula IIa, IIe, and/or IId, R^(5e) is 2substituents and are F and CN.

In some embodiments of Formula IIa and/or IId, R^(5e) is —C₁₋₂ alkyl.

In some embodiments of Formula IIa and/or IId, R^(5e) is —C₁₋₃ alkyl.

In some embodiments of Formula IIa and/or IId, R^(5e) is —C₁₋₄ alkyl.

In some embodiments of Formula IIa and/or IId, R^(5e) is —C₁₋₅ alkyl.

In some embodiments of Formula IIa and/or IId, R^(5e) is —C₁₋₆ alkyl.

In some embodiments of Formula IIa and/or IId, R^(5e) is —C₂₋₆ alkyl.

In some embodiments of Formula IIa, IIc, IId, and/or IIe, R^(5e) is—C₃₋₆ alkyl.

In some embodiments of Formula IIa and/or IId, R^(5e) is —C₄₋₆ alkyl.

In some embodiments of Formula IIa, IIe, and/or IId, R^(5e) is —C₂₋₅alkyl.

In some embodiments of Formula IIa, IIc, and/or IId, R^(5e) is —C₃₋₅alkyl.

Some additional embodiments of Formula II include compounds of Formula(IIb):

or salts, pharmaceutically acceptable salts, or prodrugs thereof.

In some embodiments of Formula IIb, Ring C is

In some embodiments of Formula IIb, Ring D is selected from the groupconsisting of phenyl and a 5-6 membered heteroaryl, wherein a carbonatom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula IIb, each R⁴ is a substituent attached toRing C and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR^(6a), CF₃, and CN.

In some embodiments of Formula IIb, each R⁵ is a substituent attached toRing D and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂,—C₁₋₃ haloalkyl, halide, —OR⁶, CF₃, and CN.

In some embodiments of Formula IIb, each R⁶ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃haloalkyl, and CF₃.

In some embodiments of Formula IIb, each R^(6a) is independentlyselected from the group consisting of unsubstituted —C₁₋₆ alkyl, —C₁₋₃haloalkyl, and CF₃.

In some embodiments of Formula IIb, each R^(6b) is independentlyselected from the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula IIb, each A is N or C.

In some embodiments of Formula IIb, at least two A must be N.

In some embodiments of Formula IIb, p is an integer of 1 to 3.

In some embodiments of Formula IIb, q is an integer of 1 to 5.

In some embodiments of Formula IIb, Ring C is selected from the groupconsisting of

Some additional embodiments of Formula II include compounds of Formula(IIc):

or salts, pharmaceutically acceptable salts, or prodrugs thereof

In some embodiments of Formula IIc, Ring C is

In some embodiments of Formula IIc, Ring D is selected from the groupconsisting of

wherein a carbon atom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula IIc, each R⁴ is a substituent attached toRing C and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR⁶, CF₃, and CN.

In some embodiments of Formula IIc, R^(5a) is a substituent attached tothe para position of phenyl and is selected from the group consisting ofunsubstituted —C₂₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₂₋₃ haloalkyl,iodide, —OR^(6a), and CN.

In some embodiments of Formula IIc, R^(5b) is a substituent attached tothe meta position of phenyl and is selected from the group consisting ofunsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₂₋₃ haloalkyl,halide, —OR^(6a), and CN.

In some embodiments of Formula IIc, R^(5a) is a substituent attached tothe ortho position of phenyl and is selected from the group consistingof unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₁₋₃ haloalkyl,F, Br, I, —OR^(6a), CF₃, and CN.

In some embodiments of Formula IIc, R^(5d) is 2-5 substituents, eachattached to the phenyl and are independently selected at each occurrencefrom the group consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(6b))₂, —C₁₋₃ haloalkyl, halide, —OR^(6a), CF₃, and CN.

In some embodiments of Formula IIc, R^(5e) is 1 substituent attached toRing D and selected from the group consisting of unsubstituted —C₂₋₅alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₁₋₃ haloalkyl, F, I, —OR⁶, CF₃, and CN.

In some embodiments of Formula IIc, R^(5f) is 1-2 substituents, eachattached to Ring D and are independently selected at each occurrencefrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(6b))₂, —C₁₋₃ haloalkyl, F, Br, I, —OR⁶, CF₃, and CN.

In some embodiments of Formula IIc, R^(5g) is 1-3 substituents, eachattached to Ring D and are independently selected at each occurrencefrom the group consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(6b))₂, —C₁₋₃ haloalkyl, halide, —OR⁶, CF₃, and CN.

In some embodiments of Formula IIc, R^(5h) is 1-2 substituents, eachattached to Ring D and are independently selected at each occurrencefrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(6b))₂, —C₁₋₃ haloalkyl, halide, —OR⁶, CF₃, and CN.

In some embodiments of Formula IIc, R^(5i) is 1-4 substituents, eachattached to Ring D and are independently selected at each occurrencefrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(6b))₂, —C₁₋₃ haloalkyl, halide, —OR⁶, CF₃, and CN.

In some embodiments of Formula IIc, each R⁶ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃haloalkyl, and CF₃.

In some embodiments of Formula IIc, each R^(6a) is independentlyselected from the group consisting of unsubstituted —C₂₋₆ alkyl, —C₁₋₃haloalkyl, and CF₃.

In some embodiments of Formula IIc, each R^(6b) is independentlyselected from the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula IIc, each J is N or C.

In some embodiments of Formula IIc, at least one J must be C.

In some embodiments of Formula IIc, Q is S or O.

In some embodiments of Formula IIc, each U is N or C.

In some embodiments of Formula IIc, at least one U must be N and atleast one U must be C.

In some embodiments of Formula IIc, p is an integer of 1 to 3.

In some embodiments of Formula IIc, Ring D is selected from the groupconsisting of

wherein a carbon atom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula IIc, R^(5f) is H.

In some embodiments of Formula IIc, R^(5f) is a halide.

In some embodiments of Formula IIc, R^(5f) is F.

In some embodiments of Formula IIc, R^(5f) is Cl.

In some embodiments of Formula IIc, R^(5f) is Me.

In some embodiments of Formula IIc, R^(5f) is OH.

In some embodiments of Formula IIc, R^(5f) is OMe.

In some embodiments of Formula IIc, R^(5f) is CF₃.

In some embodiments of Formula IIc, R^(5f) is CN.

In some embodiments of Formula IIc, R^(5f) is 1 substituent and is F.

In some embodiments of Formula IIc, R^(5f) is 2 substituents and areboth F.

In some embodiments of Formula IIc, R^(5f) is 1 substituent and is Me.

In some embodiments of Formula IIc, R^(5f) is 2 substituents and areboth Me.

In some embodiments of Formula IIc, R^(5f) is 1 substituent and is CF₃.

In some embodiments of Formula IIc, R^(5f) is 2 substituents and areboth CF₃.

In some embodiments of Formula IIc, R^(5f) is 1 substituent and is OMe.

In some embodiments of Formula IIc, R^(5f) is 2 substituents and areboth OMe.

In some embodiments of Formula IIc, R^(5f) is 2 substituents and are Fand Me.

In some embodiments of Formula IIc, R^(5f) is 2 substituents and are Fand CF₃.

In some embodiments of Formula IIc, R^(5f) is 2 substituents and are Fand OMe.

In some embodiments of Formula IIc, R^(5f) is 1 substituent and is CN.

In some embodiments of Formula IIc, R^(5f) is 2 substituents and areboth CN.

In some embodiments of Formula IIc, R^(5f) is 2 substituents and are Fand CN.

In some embodiments of Formula IIc, R^(5f) is —C₁₋₂ alkyl.

In some embodiments of Formula IIc, R^(5f) is —C₁₋₃ alkyl.

In some embodiments of Formula IIc, R^(5f) is —C₁₋₄ alkyl.

In some embodiments of Formula IIc, R^(5f) is —C₁₋₅ alkyl.

In some embodiments of Formula IIc, R^(5f) is —C₁₋₆ alkyl.

In some embodiments of Formula IIc, R^(5f) is —C₂₋₆ alkyl.

In some embodiments of Formula IIc, R^(5f) is —C₃₋₆ alkyl.

In some embodiments of Formula IIc, R^(5f) is —C₄₋₆ alkyl.

In some embodiments of Formula IIc, R^(5f) is —C₂₋₅ alkyl.

In some embodiments of Formula IIc, R^(5f) is —C₃₋₅ alkyl.

In some embodiments of Formula IIc, R^(5g) is a halide.

In some embodiments of Formula IIc, R^(5g) is F.

In some embodiments of Formula IIc, R^(5g) is Cl.

In some embodiments of Formula IIc, R^(5g) is Me.

In some embodiments of Formula IIc, R^(5g) is OH.

In some embodiments of Formula IIc, R^(5g) is OMe.

In some embodiments of Formula IIc, R^(5g) is CF₃.

In some embodiments of Formula IIc, R^(5g) is CN.

In some embodiments of Formula IIc, R^(5g) is 1 substituent and is F.

In some embodiments of Formula IIc, R^(5g) is 2 substituents and areboth F.

In some embodiments of Formula IIc, R^(5g) is 1 substituent and is Me.

In some embodiments of Formula IIc, R^(5g) is 2 substituents and areboth Me.

In some embodiments of Formula IIc, R^(5g) is 1 substituent and is CF₃.

In some embodiments of Formula IIc, R^(5g) is 2 substituents and areboth CF₃.

In some embodiments of Formula IIc, R^(5g) is 1 substituent and is OMe.

In some embodiments of Formula IIc, R^(5g) is 2 substituents and areboth OMe.

In some embodiments of Formula IIc, R^(5g) is 2 substituents and are Fand Me.

In some embodiments of Formula IIc, R^(5g) is 2 substituents and are Fand CF₃.

In some embodiments of Formula IIc, R^(5g) is 2 substituents and are Fand OMe.

In some embodiments of Formula IIc, R^(5g) is 1 substituent and is CN.

In some embodiments of Formula IIc, R^(5g) is 2 substituents and areboth CN.

In some embodiments of Formula IIc, R^(5g) is 2 substituents and are Fand CN.

In some embodiments of Formula IIc, R^(5g) is —C₁₋₂ alkyl.

In some embodiments of Formula IIc, R^(5g) is —C₁₋₃ alkyl.

In some embodiments of Formula IIc, R^(5g) is —C₁₋₄ alkyl.

In some embodiments of Formula IIc, R^(5g) is —C₁₋₅ alkyl.

In some embodiments of Formula IIc, R^(5g) is —C₁₋₆ alkyl.

In some embodiments of Formula IIc, R^(5g) is —C₂₋₆ alkyl.

In some embodiments of Formula IIc, R^(5g) is —C₃₋₆ alkyl.

In some embodiments of Formula IIc, R^(5g) is —C₄₋₆ alkyl.

In some embodiments of Formula IIc, R^(5g) is —C₂₋₅ alkyl.

In some embodiments of Formula IIc, R^(5g) is —C₃₋₅ alkyl.

In some embodiments of Formula IIc, R^(5i) is H.

In some embodiments of Formula IIc, R^(5i) is a halide.

In some embodiments of Formula IIc, R^(5i) is F.

In some embodiments of Formula IIc, R^(5i) is Cl.

In some embodiments of Formula IIc, R^(5i) is Me.

In some embodiments of Formula IIc, R^(5i) is OH.

In some embodiments of Formula IIc, R^(5i) is OMe.

In some embodiments of Formula IIc, R^(5i) is CF₃.

In some embodiments of Formula IIc, R^(5i) is CN.

In some embodiments of Formula IIc, R^(5i) is 1 substituent and is F.

In some embodiments of Formula IIc, R^(5i) is 2 substituents and areboth F.

In some embodiments of Formula IIc, R^(5i) is 1 substituent and is Me.

In some embodiments of Formula IIc, R^(5i) is 2 substituents and areboth Me.

In some embodiments of Formula IIc, R^(5i) is 1 substituent and is CF₃.

In some embodiments of Formula IIc, R^(5i) is 2 substituents and areboth CF₃.

In some embodiments of Formula IIc, R^(5i) is 1 substituent and is OMe.

In some embodiments of Formula IIc, R^(5i) is 2 substituents and areboth OMe.

In some embodiments of Formula IIc, R^(5i) is 2 substituents and are Fand Me.

In some embodiments of Formula IIc, R^(5i) is 2 substituents and are Fand CF₃.

In some embodiments of Formula IIc, R^(5i) is 2 substituents and are Fand OMe.

In some embodiments of Formula IIc, R^(5i) is 1 substituent and is CN.

In some embodiments of Formula IIc, R^(5i) is 2 substituents and areboth CN.

In some embodiments of Formula IIc, R^(5i) is 2 substituents and are Fand CN.

In some embodiments of Formula IIc, R^(5i) is —C₁₋₂ alkyl.

In some embodiments of Formula IIc, R^(5i) is —C₁₋₃ alkyl.

In some embodiments of Formula IIc, R^(5i) is —C₁₋₄ alkyl.

In some embodiments of Formula IIc, R^(5i) is —C₁₋₅ alkyl.

In some embodiments of Formula IIc, R^(5i) is —C₁₋₆ alkyl.

In some embodiments of Formula IIc, R^(5i) is —C₂₋₆ alkyl.

In some embodiments of Formula IIc, R^(5i) is —C₃₋₆ alkyl.

In some embodiments of Formula IIc, R^(5i) is —C₄₋₆ alkyl.

In some embodiments of Formula IIc, R^(5i) is —C₂₋₅ alkyl.

In some embodiments of Formula IIc, R^(5i) is —C₃₋₅ alkyl.

Some additional embodiments of Formula II include compounds of Formula(IId):

or salts, pharmaceutically acceptable salts, or prodrugs thereof.

In some embodiments of Formula IId, Ring C is

In some embodiments of Formula IId, Ring D is selected from the groupconsisting of

wherein a carbon atom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula IId, each R⁴ is a substituent attached toRing C and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR⁶, CF₃, and CN.

In some embodiments of Formula IId, R^(5a) is 1 substituent attached toRing D and selected from the group consisting of unsubstituted —C₂₋₆alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₁₋₃ haloalkyl, halide, —OR^(6a), andCN.

In some embodiments of Formula IId, R^(5b) is 1-4 substituents, eachattached to Ring D and are independently selected at each occurrencefrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(6b))₂, —C₁₋₃ haloalkyl, halide, —OR^(6a), CF₃, and CN.

In some embodiments of Formula IId, R^(5c) is 1-3 substituents, eachattached to Ring D and are independently selected at each occurrencefrom the group consisting of unsubstituted —C₂₋₅ alkyl, —CH₂OH,—CH₂N(R^(6b))₂, haloalkyl, halide, —OR⁶, CF₃, and CN.

In some embodiments of Formula IId, R^(5d) is 1-2 substituents, eachattached to Ring D and are independently selected at each occurrencefrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(6b))₂, —C₁₋₃ haloalkyl, halide, —OR⁶, CF₃, and CN.

In some embodiments of Formula IId, R^(5e) is 1-4 substituents, eachattached to Ring D and are independently selected at each occurrencefrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(6b))₂, haloalkyl, halide, —OR⁶, CF₃, and CN.

In some embodiments of Formula IId, each R⁶ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃haloalkyl, and CF₃.

In some embodiments of Formula IId, each R^(6a) is independentlyselected from the group consisting of unsubstituted —C₂₋₆ alkyl, —C₁₋₃haloalkyl, and CF₃.

In some embodiments of Formula IId, each R^(6b) is independentlyselected from the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula IId, each J is N or C.

In some embodiments of Formula IId, at least one J must be N and atleast one J must be C.

In some embodiments of Formula IId, Q is S or O.

In some embodiments of Formula IId, each U is N or C.

In some embodiments of Formula IId, at least one U must be C.

In some embodiments of Formula IId, p is an integer of 1 to 3.

In some embodiments of Formula IId, Ring D is selected from the groupconsisting of

wherein a carbon atom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula IId, R^(5b) is H.

In some embodiments of Formula IId and/or IIe, R^(5d) is H.

Some additional embodiments of Formula II include compounds of Formula(IIe):

or salts, pharmaceutically acceptable salts, or prodrugs thereof.

In some embodiments of Formula IIe, Ring C is

wherein a carbon atom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula IIe, Ring D is selected from the groupconsisting of

wherein a carbon atom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula IIe, each R⁴ is a substituent attached toRing C and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR⁶, CF₃, and CN.

In some embodiments of Formula IIe, R^(5a) is a substituent attached tothe para position of phenyl and is selected from the group consisting ofH, unsubstituted C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₁₋₃ haloalkyl, F,Br, I, —OR⁶, CF₃, and CN.

In some embodiments of Formula IIe, R^(5b) is 1-4 substituents, eachattached to Ring D and are independently selected at each occurrencefrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(6b))₂, —C₁₋₃ haloalkyl, halide, —OR⁶, CF₃, and CN.

In some embodiments of Formula IIe, R^(5c) is 1-4 substituents, eachattached to Ring D and are independently selected at each occurrencefrom the group consisting of unsubstituted —C₂₋₅ alkyl, —CH₂OH,—CH₂N(R^(6b))₂, —C₁₋₃ haloalkyl, halide, —OR⁶, CF₃, and CN.

In some embodiments of Formula IIe, R^(5d) is 1-2 substituents, eachattached to Ring D and are independently selected at each occurrencefrom the group consisting of H, unsubstituted —C₂₋₆ alkyl, —CH₂OH,—CH₂N(R^(6b))₂, —C₁₋₃ haloalkyl, halide, —OR^(6a), CF₃, and CN.

In some embodiments of Formula IIe, each R⁶ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃haloalkyl, and CF₃.

In some embodiments of Formula IIe, each R^(6a) is independentlyselected from the group consisting of unsubstituted —C₁₋₆ alkyl, —C₁₋₃haloalkyl, and CF₃.

In some embodiments of Formula IIe, each R^(6b) is independentlyselected from the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula IIe, each A is N or C.

In some embodiments of Formula IIe, at least one A must be C.

In some embodiments of Formula IIe, each U is N or C.

In some embodiments of Formula IIe, at least one U must be N and atleast one U must be C.

In some embodiments of Formula IIe, p is an integer of 1 to 4.

In some embodiments of Formula IIe, Ring C is selected from the groupconsisting of

In some embodiments of Formula IIe, Ring D is selected from the groupconsisting of

wherein a carbon atom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula IIe, R^(5a) is 1 substituent and is OMe.

In some embodiments of Formula IIe, R^(5a) is 2 substituents and bothare OMe.

In some embodiments of Formula IIe, R^(5a) is 2 substituents and are Fand OMe.

In some embodiments of Formula IIe and/or IIf, R^(5b) is H.

In some embodiments of Formula IIe and/or IIf, R^(5b) is 1 substituentand is OMe.

In some embodiments of Formula IIe and/or IIf, R^(5b) is 2 substituentsand both are OMe.

In some embodiments of Formula IIe and/or IIf, R^(5b) is 2 substituentsand are F and OMe.

Some additional embodiments of Formula II include compounds of Formula(IIf):

or salts, pharmaceutically acceptable salts, or prodrugs thereof.

In some embodiments of Formula IIf, Ring C is

wherein a carbon atom on the ring is attached to the carbonyl carbon.

In some embodiments of Formula IIf, Ring D is selected from the groupconsisting of

and a 5-membered heteroarylR^(5b), wherein a carbon atom on the ring isattached to the carbonyl carbon.

In some embodiments of Formula IIf, each R⁴ is a substituent attached toRing C and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR⁶, CF₃, and CN.

In some embodiments of Formula IIf, R^(5a) is 1-5 substituents, eachattached to phenyl and selected from the group consisting of H,unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₁₋₃ haloalkyl,halide, —OR^(6a), CF₃, and CN.

In some embodiments of Formula IIf, R^(5b) is 1-4 substituents, eachattached to Ring D and are independently selected at each occurrencefrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(6b))₂, —C₁₋₃ haloalkyl, halide, —OR⁶, CF₃, and CN.

In some embodiments of Formula III, each R⁶ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃haloalkyl, and CF₃.

In some embodiments of Formula IIf, each R^(6a) is independentlyselected from the group consisting of unsubstituted —C₂₋₆ alkyl, —C₁₋₃haloalkyl, and CF₃.

In some embodiments of Formula IIf, each R^(6b) is independentlyselected from the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula IIf, each A is N or C.

In some embodiments of Formula IIf, at least one A must be N and atleast one A must be C.

In some embodiments of Formula IIf, Q is S or O.

In some embodiments of Formula IIf, p is an integer of 1 to 4.

In some embodiments of Formula IIf, Ring C is selected from the groupconsisting of

In some embodiments of Formula III, Ring D is selected from the groupconsisting of

wherein a carbon atom on the ring is attached to the carbonyl carbon.

Some embodiments of the present disclosure include compounds of Formula(III):

or salts, pharmaceutically acceptable salts or prodrugs thereof

In some embodiments of Formula III, each R⁷ is a substituent attached tothe phenyl ring and is independently selected at each occurrence fromthe group consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(9a))₂, —C₁₋₃ haloalkyl, halide, —OR⁹, CF₃, and CN.

In some embodiments of Formula III, each R⁸ is a substituent attached tothe phenyl ring and is independently selected at each occurrence fromthe group consisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(9a))₂, —C₁₋₃ haloalkyl, halide, —OR⁹, CF₃, and CN.

In some embodiments of Formula III, each R⁹ is independently selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃haloalkyl, and CF₃.

In some embodiments of Formula III, each R^(9a) is independentlyselected from the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula III, each q is an integer of 1 to 5.

In some embodiments of Formula III, each R⁷ is independently selectedfrom the group consisting of F, Cl, Me, OMe, OH, CF₃ and CN.

In some embodiments of Formula III, R⁷ is a halide.

In some embodiments of Formula III, R⁷ is F.

In some embodiments of Formula III, R⁷ is Cl.

In some embodiments of Formula III, R⁷ is Me.

In some embodiments of Formula III, R⁷ is OH.

In some embodiments of Formula III, R⁷ is OMe.

In some embodiments of Formula III, R⁷ is CF₃.

In some embodiments of Formula III, R⁷ is CN.

In some embodiments of Formula III, q is an integer from 1-4.

In some embodiments of Formula III, q is an integer from 1-3.

In some embodiments of Formula III, q is an integer from 1-2.

In some embodiments of Formula III, q is 2.

In some embodiments of Formula III, q is 1.

In some embodiments of Formula III, R⁷ is F; and q is 1.

In some embodiments of Formula III, R⁷ is F; and q is 2.

In some embodiments of Formula III, R⁷ is Me; and q is 1.

In some embodiments of Formula III, R⁷ is Me; and q is 2.

In some embodiments of Formula III, R⁷ is CF₃; and q is 1.

In some embodiments of Formula III, R⁷ is CF₃; and q is 2.

In some embodiments of Formula III, R⁷ is OMe; and q is 1.

In some embodiments of Formula III, R⁷ is OMe; and q is 2.

In some embodiments of Formula III, R⁷ is F and Me; and q is 2.

In some embodiments of Formula III, R⁷ is F and CF₃; and q is 2.

In some embodiments of Formula III, R⁷ is F and OMe; and q is 2.

In some embodiments of Formula III, R⁷ is CN; and q is 1.

In some embodiments of Formula III, R⁷ is CN; and q is 2.

In some embodiments of Formula III, R⁷ is F and CN; and q is 2.

In some embodiments of Formula III, R⁷ is —C₁₋₂ alkyl.

In some embodiments of Formula III, R⁷ is —C₁₋₃ alkyl.

In some embodiments of Formula III, R⁷ is —C₁₋₄ alkyl.

In some embodiments of Formula III, R⁷ is —C₁₋₅ alkyl.

In some embodiments of Formula III, R⁷ is —C₁₋₆ alkyl.

In some embodiments of Formula III, R⁷ is —C₂₋₆ alkyl.

In some embodiments of Formula III, R⁷ is —C₃₋₆ alkyl.

In some embodiments of Formula III, R⁷ is —C₄₋₆ alkyl.

In some embodiments of Formula III, R⁷ is —C₂₋₅ alkyl.

In some embodiments of Formula III, R⁷ is —C₃₋₅ alkyl.

In some embodiments of Formula III, each R⁸ is independently selectedfrom the group consisting of H, F, Cl, Me, OMe, OH, CF₃ and CN.

In some embodiments of Formula III, R⁸ is H.

In some embodiments of Formula III, R⁸ is a halide.

In some embodiments of Formula III, R⁸ is F.

In some embodiments of Formula III, R⁸ is Cl.

In some embodiments of Formula III, R⁸ is Me.

In some embodiments of Formula III, R⁸ is OH.

In some embodiments of Formula III, R⁸ is OMe.

In some embodiments of Formula III, R⁸ is CF₃.

In some embodiments of Formula III, R⁸ is CN.

In some embodiments of Formula III, q is an integer from 1-4.

In some embodiments of Formula III, q is an integer from 1-3.

In some embodiments of Formula III, q is an integer from 1-2.

In some embodiments of Formula III, q is 2.

In some embodiments of Formula III, q is 1.

In some embodiments of Formula III, R⁸ is F; and q is 1.

In some embodiments of Formula III, R⁸ is F; and q is 2.

In some embodiments of Formula III, R⁸ is Me; and q is 1.

In some embodiments of Formula III, R⁸ is Me; and q is 2.

In some embodiments of Formula III, R⁸ is CF₃; and q is 1.

In some embodiments of Formula III, R⁸ is CF₃; and q is 2.

In some embodiments of Formula III, R⁸ is OMe; and q is 1.

In some embodiments of Formula III, R⁸ is OMe; and q is 2.

In some embodiments of Formula III, R⁸ is F and Me; and q is 2.

In some embodiments of Formula III, R⁸ is F and CF₃; and q is 2.

In some embodiments of Formula III, R⁸ is F and OMe; and q is 2.

In some embodiments of Formula III, R⁸ is CN; and q is 1.

In some embodiments of Formula III, R⁸ is CN; and q is 2.

In some embodiments of Formula III, R⁸ is F and CN; and q is 2.

In some embodiments of Formula III, R⁸ is —C₁₋₂ alkyl.

In some embodiments of Formula III, R⁸ is —C₁₋₃ alkyl.

In some embodiments of Formula III, R⁸ is —C₁₋₄ alkyl.

In some embodiments of Formula III, R⁸ is —C₁₋₅ alkyl.

In some embodiments of Formula III, R⁸ is —C₁₋₆ alkyl.

In some embodiments of Formula III, R⁸ is —C₂₋₆ alkyl.

In some embodiments of Formula III, R⁸ is —C₃₋₆ alkyl.

In some embodiments of Formula III, R⁸ is —C₄₋₆ alkyl.

In some embodiments of Formula III, R⁸ is —C₂₋₅ alkyl.

In some embodiments of Formula III, R⁸ is —C₃₋₅ alkyl.

In some embodiments of Formula III, R⁹ is —C₁₋₂ alkyl.

In some embodiments of Formula III, R⁹ is —C₁₋₃ alkyl.

In some embodiments of Formula III, R⁹ is —C₁₋₄ alkyl.

In some embodiments of Formula III, R⁹ is —C₁₋₅ alkyl.

In some embodiments of Formula III, R⁹ is —C₁₋₆ alkyl.

In some embodiments of Formula III, R⁹ is —C₂₋₆ alkyl.

In some embodiments of Formula III, R⁹ is —C₃₋₆ alkyl.

In some embodiments of Formula III, R⁹ is —C₄₋₆ alkyl.

In some embodiments of Formula III, R⁹ is —C₂₋₅ alkyl.

In some embodiments of Formula III, R⁹ is —C₃₋₅ alkyl.

In some embodiments of Formula III, R⁷ and/or R⁸ is —CH₂OH.

In some embodiments of Formula III, R⁷ and/or R⁸ is —CH₂N(R^(9a))₂.

In some embodiments of Formula III, R⁷ and/or R⁸ is —CH₂NH₂.

In some embodiments of Formula III, R⁷ and/or R⁸ is —CH₂NHMe₂.

In some embodiments of Formula III, R⁷ and/or R⁸ is —CH₂NMe₂.

In some embodiments of Formula III, R⁷ and/or R⁸ is —CH₂NHEt.

In some embodiments of Formula III, R⁷ and/or R⁸ is —CH₂N(Me)(Et).

In some embodiments of Formula III, R⁷ and/or R⁸ is —CH₂NEt₂.

Some additional embodiments of Formula III include compounds of Formula(IIIa):

or salts, pharmaceutically acceptable salts, or prodrugs thereof.

In some embodiments of Formula IIIa, R¹⁰ is selected from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR¹³, CF₃, and CN.

In some embodiments of Formula IIIa, R¹¹ is selected from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(13b))₂, —C₁₋₃haloalkyl, halide, —OR¹³, CF₃, and CN.

In some embodiments of Formula IIIa, each R¹² is a substituent attachedto the phenyl ring and is independently selected at each occurrence fromthe group consisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(13b))₂, —C₁₋₃ haloalkyl, halide, —OR¹³, CF₃, and CN.

In some embodiments of Formula IIIa, each R¹³ is independently selectedfrom the group consisting of unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl,and CF₃.

In some embodiments of Formula IIIa, each R^(13b) is independentlyselected from the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula IIIa, each q is an integer of 1 to 5.

In some embodiments of Formula IIIa, there is the proviso that acompound Formula IIIa is not a compound selected from the groupconsisting of:

In some embodiments of Formula IIIa and/or IIIc, R¹⁰ is selected fromthe group consisting of H, F, Cl, Me, OMe, CF₃, and CN.

In some embodiments of Formula IIIa and/or IIIc, R¹¹ is selected fromthe group consisting of F, Cl, Me, OMe, CF₃, and CN.

In some embodiments of Formula IIIa and/or IIIc, R¹⁰ is H; and R¹¹ is F.

In some embodiments of Formula IIIa and/or IIIc, R¹⁰ is H; and R¹¹ isCl.

In some embodiments of Formula IIIa and/or IIIc, R¹⁰ is H; and R¹¹ isMe.

In some embodiments of Formula IIIa and/or IIIc, R¹⁰ is H; and R¹¹ isOMe.

In some embodiments of Formula IIIa and/or IIIc, R¹⁰ is H; and R^(u) isCF₃.

In some embodiments of Formula IIIa and/or IIIc, R¹⁰ is H; and R¹¹ isCN.

In some embodiments of Formula IIIa and/or IIIc, R¹⁰ is F; and R¹¹ is F.

In some embodiments of Formula IIIa and/or IIIc, R¹⁰ is F; and R¹¹ isCl.

In some embodiments of Formula IIIa and/or IIIc, R¹⁰ is F; and R¹¹ isMe.

In some embodiments of Formula IIIa and/or IIIc, R¹⁰ is F; and R¹¹ isOMe.

In some embodiments of Formula IIIa and/or IIIc, R¹⁰ is F; and R¹¹ isCF₃.

In some embodiments of Formula IIIa and/or IIIc, R¹⁰ is F; and R¹¹ isCN.

In some embodiments of Formula IIIa and/or IIIc, R¹⁰ is —C₁₋₂ alkyl.

In some embodiments of Formula IIIa and/or IIIc, R¹⁰ is —C₁₋₃ alkyl.

In some embodiments of Formula IIIa and/or IIIc, R¹⁰ is —C₁₋₄ alkyl.

In some embodiments of Formula IIIa and/or IIIc, R¹⁰ is —C₁₋₅ alkyl.

In some embodiments of Formula IIIa and/or IIIc, R¹⁰ is —C₁₋₆ alkyl.

In some embodiments of Formula IIIa and/or IIIc, R¹⁰ is —C₂₋₆ alkyl.

In some embodiments of Formula IIIa and/or IIIc, R¹⁰ is —C₃₋₆ alkyl.

In some embodiments of Formula IIIa and/or IIIc, R¹⁰ is —C₄₋₆ alkyl.

In some embodiments of Formula IIIa and/or IIIc, R¹⁰ is —C₂₋₅ alkyl.

In some embodiments of Formula IIIa and/or IIIc, R¹⁰ is —C₃₋₅ alkyl.

In some embodiments of Formula IIIa and/or IIIc, R¹¹ is —C₁₋₂ alkyl.

In some embodiments of Formula IIIa and/or IIIc, R¹¹ is —C₁₋₃ alkyl.

In some embodiments of Formula IIIa and/or IIIc, R¹¹ is —C₁₋₄ alkyl.

In some embodiments of Formula IIIa and/or IIIc, R¹¹ is —C₁₋₅ alkyl.

In some embodiments of Formula IIIa and/or IIIc, R¹¹ is —C₁₋₆ alkyl.

In some embodiments of Formula IIIa and/or IIIc, R¹¹ is —C₂₋₆ alkyl.

In some embodiments of Formula IIIa and/or IIIc, R¹¹ is —C₃₋₆ alkyl.

In some embodiments of Formula IIIa and/or IIIc, R¹¹ is —C₄₋₆ alkyl.

In some embodiments of Formula IIIa and/or IIIc, R¹¹ is —C₂₋₅ alkyl.

In some embodiments of Formula IIIa and/or IIIc, R¹¹ is —C₃₋₅ alkyl.

In some embodiments of Formula IIIa, each R¹² is selected from the groupconsisting of H, F, Cl, Me, OMe, CF₃, and CN.

In some embodiments of Formula IIIa, R¹² is H.

In some embodiments of Formula IIIa, R¹² is a halide.

In some embodiments of Formula IIIa, R¹² is F.

In some embodiments of Formula IIIa, R¹² is Cl.

In some embodiments of Formula IIIa, R¹² is Me.

In some embodiments of Formula IIIa, R¹² is OH.

In some embodiments of Formula IIIa, R¹² is OMe.

In some embodiments of Formula IIIa, R¹² is CF₃.

In some embodiments of Formula IIIa, R¹² is CN.

In some embodiments of Formula IIIa and/or IIIc, q is an integer from1-4.

In some embodiments of Formula IIIa and/or IIIc, q is an integer from1-3.

In some embodiments of Formula IIIa, q is an integer from 1-2.

In some embodiments of Formula IIIa and/or IIIc, q is 2.

In some embodiments of Formula IIIa and/or IIIc, q is 1.

In some embodiments of Formula IIIa, R¹² is F; and q is 1.

In some embodiments of Formula IIIa, R¹² is F; and q is 2.

In some embodiments of Formula IIIa, R¹² is Me; and q is 1.

In some embodiments of Formula IIIa, R¹² is Me; and q is 2.

In some embodiments of Formula IIIa, R¹² is CF₃; and q is 1.

In some embodiments of Formula IIIa, R¹² is CF₃; and q is 2.

In some embodiments of Formula IIIa, R¹² is OMe; and q is 1.

In some embodiments of Formula IIIa, R¹² is OMe; and q is 2.

In some embodiments of Formula IIIa, R¹² is F and Me; and q is 2.

In some embodiments of Formula IIIa, R¹² is F and CF₃; and q is 2.

In some embodiments of Formula IIIa, R¹² is F and OMe; and q is 2.

In some embodiments of Formula IIIa, R¹² is CN; and q is 1.

In some embodiments of Formula IIIc, R¹² is CN; and q is 2.

In some embodiments of Formula IIIa, R¹² is F and CN; and q is 2.

In some embodiments of Formula IIIa, R¹² is F or Cl; q is I.

In some embodiments of Formula IIIa, R¹² is —C₁₋₂ alkyl.

In some embodiments of Formula IIIa, R¹² is —C₁₋₃ alkyl.

In some embodiments of Formula IIIa, R¹² is —C₁₋₄ alkyl.

In some embodiments of Formula IIIa, R¹² is —C₁₋₅ alkyl.

In some embodiments of Formula IIIa, R¹² is —C₁₋₆ alkyl.

In some embodiments of Formula IIIa, R¹² is —C₂₋₆ alkyl.

In some embodiments of Formula IIIa, R¹² is —C₃₋₆ alkyl.

In some embodiments of Formula IIIa, R¹² is —C₄₋₆ alkyl.

In some embodiments of Formula IIIa, R¹² is —C₂₋₅ alkyl.

In some embodiments of Formula IIIa, R¹² is —C₃₋₅ alkyl.

In some embodiments of Formula IIIa and/or IIIc, R¹¹ is —CH₂OH.

In some embodiments of Formula IIIa and/or IIIc, R¹¹ is —CH₂N(R¹³)₂.

In some embodiments of Formula IIIa and/or IIIc, R¹¹ is —CH₂NH₂.

In some embodiments of Formula IIIa and/or IIIc, R¹¹ is —CH₂NHMe.

In some embodiments of Formula IIIa and/or IIIc, R¹¹ is —CH₂NMe₂.

In some embodiments of Formula IIIa and/or IIIc, R¹¹ is —CH₂NHEt.

In some embodiments of Formula IIIa and/or IIIc, R¹¹ is —CH₂N(Me)(Et).

In some embodiments of Formula IIIa and/or IIIc, R¹¹ is —CH₂NEt₂.

In some embodiments of Formula IIIa and/or IIIc, R¹³ is —C₁₋₂ alkyl.

In some embodiments of Formula IIIa and/or IIIc, R¹³ is —C₁₋₃ alkyl.

In some embodiments of Formula IIIa and/or IIIc, R¹³ is —C₁₋₄ alkyl.

In some embodiments of Formula IIIa and/or IIIc, R¹³ is —C₁₋₅ alkyl.

In some embodiments of Formula IIIa and/or IIIc, R¹³ is —C₁₋₆ alkyl.

In some embodiments of Formula IIIa and/or IIIc, R¹³ is —C₂₋₆ alkyl.

In some embodiments of Formula IIIa and/or IIIc, R¹³ is —C₃₋₆ alkyl.

In some embodiments of Formula IIIa and/or IIIc, R¹³ is —C₄₋₆ alkyl.

In some embodiments of Formula IIIa and/or IIIc, R¹³ is —C₂₋₅ alkyl.

In some embodiments of Formula IIIa and/or IIIc, R¹³ is —C₃₋₅ alkyl.

Some additional embodiments of Formula III include compounds of Formula(IIIb):

or salts, pharmaceutically acceptable salts, or prodrugs thereof.

In some embodiments of Formula IIIb, R¹⁴ is selected from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, and CF₃.

In some embodiments of Formula IIIb, R¹⁵ is selected from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, and CF₃.

In some embodiments of Formula IIIb, each R¹⁶ is a substituent attachedto the phenyl ring and is independently selected at each occurrence fromthe group consisting of H, unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(17b))₂, —C₁₋₃ haloalkyl, halide, —OR¹⁷, CF₃, and CN.

In some embodiments of Formula IIIb, each R¹⁷ is independently selectedfrom the group consisting of unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl,and CF₃.

In some embodiments of Formula IIIb, each R^(17b) is independentlyselected from the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula IIIb, each q is an integer of 1 to 5.

In some embodiments of Formula IIIb, there is the proviso that acompound of Formula IIIb is not a compound selected from the groupconsisting of:

In some embodiments of Formula IIIb and/or IIId, R¹⁴ is Me

In some embodiments of Formula IIIb and/or IIId, R¹⁴ is Et.

In some embodiments of Formula IIIb and/or IIId, R¹⁴ is —C₁₋₂ alkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁴ is —C₁₋₃ alkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁴ is —C₁₋₄ alkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁴ is —C₁₋₅ alkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁴ is —C₁₋₆ alkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁴ is —C₂₋₆ alkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁴ is —C₃₋₆ alkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁴ is —C₄₋₆ alkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁴ is —C₂₋₅ alkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁴ is —C₃₋₅ alkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁴ is —C₁₋₂ haloalkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁴ is —C₁₋₃ haloalkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁴ is —C₂₋₃ haloalkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁴ is CF₃.

In some embodiments of Formula IIIb and/or IIId, R¹⁵ is Me

In some embodiments of Formula IIIb and/or IIId, R¹⁵ is Et.

In some embodiments of Formula IIIb and/or IIId, R¹⁵ is —C₁₋₂ alkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁵ is —C₁₋₃ alkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁵ is —C₁₋₄ alkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁵ is —C₁₋₅ alkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁵ is —C₁₋₆ alkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁵ is —C₂₋₆ alkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁵ is —C₃₋₆ alkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁵ is —C₄₋₆ alkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁵ is —C₂₋₅ alkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁵ is —C₃₋₅ alkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁵ is —C₁₋₂ haloalkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁵ is —C₁₋₃ haloalkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁵ is —C₂₋₃ haloalkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁵ is CF₃.

In some embodiments of Formula IIIb, each R¹⁶ is selected from the groupconsisting of H, F, Cl, Me, OMe, CF₃, and CN.

In some embodiments of Formula IIIb, R¹⁶ is H.

In some embodiments of Formula IIIb and/or IIId, R¹⁶ is a halide.

In some embodiments of Formula IIIb and/or IIId, R¹⁶ is F.

In some embodiments of Formula IIIb and/or IIId, R¹⁶ is Cl.

In some embodiments of Formula IIIb and/or IIId, R¹⁶ is Me.

In some embodiments of Formula IIIb, R¹⁶ is OH.

In some embodiments of Formula IIIb, R¹⁶ is OMe.

In some embodiments of Formula IIIb and/or IIId, R¹⁶ is CF₃.

In some embodiments of Formula IIIb and/or IIId, R¹⁶ is CN.

In some embodiments of Formula IIIb and/or IIId, q is an integer from1-4.

In some embodiments of Formula IIIb and/or IIId, q is an integer from1-3.

In some embodiments of Formula IIIb and/or IIId, q is an integer from1-2.

In some embodiments of Formula IIIb and/or IIId, q is 2.

In some embodiments of Formula IIIb and/or IIId, q is 1.

In some embodiments of Formula IIIb and/or IIId, R¹⁶ is F; and q is 1.

In some embodiments of Formula IIIb and/or IIId, R¹⁶ is F; and q is 2.

In some embodiments of Formula IIIb and/or IIId, R¹⁶ is Me; and q is 1.

In some embodiments of Formula IIIb and/or IIId, R¹⁶ is Me; and q is 2.

In some embodiments of Formula IIIb and/or IIId, R¹⁶ is CF₃; and q is 1.

In some embodiments of Formula IIIb and/or IIId, R¹⁶ is CF₃; and q is 2.

In some embodiments of Formula IIIb, R¹⁶ is OMe; and q is 1.

In some embodiments of Formula IIIb, R¹⁶ is OMe; and q is 2.

In some embodiments of Formula IIIb and/or IIId, R¹⁶ is F and Me; and qis 2.

In some embodiments of Formula IIIb and/or IIId, R¹⁶ is F and CF₃; and qis 2.

In some embodiments of Formula IIIb, R¹⁶ is F and OMe; and q is 2.

In some embodiments of Formula IIIb and/or IIId, R¹⁶ is CN; and q is 1.

In some embodiments of Formula IIIb and/or IIId, R¹⁶ is CN; and q is 2.

In some embodiments of Formula IIIb and/or IIId, R¹⁶ is F and CN; and qis 2.

In some embodiments of Formula IIIb and/or IIId, R¹⁶ is F or Cl; q is 1.

In some embodiments of Formula IIIb and/or IIId, R¹⁶ is —C₁₋₂ alkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁶ is —C₁₋₃ alkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁶ is —C₁₋₄ alkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁶ is —C₁₋₅ alkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁶ is —C₁₋₆ alkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁶ is —C₂₋₆ alkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁶ is —C₃₋₆ alkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁶ is —C₄₋₆ alkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁶ is —C₂₋₅ alkyl.

In some embodiments of Formula IIIb and/or IIId, R¹⁶ is —C₃₋₅ alkyl.

In some embodiments of Formula IIIb, R¹⁷ is —C₁₋₂ alkyl.

In some embodiments of Formula IIIb, R¹⁷ is —C₁₋₃ alkyl.

In some embodiments of Formula IIIb, R¹⁷ is —C₁₋₄ alkyl.

In some embodiments of Formula IIIb, R¹⁷ is —C₁₋₅ alkyl.

In some embodiments of Formula IIIb, R¹⁷ is —C₁₋₆ alkyl.

In some embodiments of Formula IIIb, R¹⁷ is —C₂₋₆ alkyl.

In some embodiments of Formula IIIb, R¹⁷ is —C₃₋₆ alkyl.

In some embodiments of Formula IIIb, R¹⁷ is —C₄₋₆ alkyl.

In some embodiments of Formula IIIb, R¹⁷ is —C₂₋₅ alkyl.

In some embodiments of Formula IIIb, R¹⁷ is —C₃₋₅ alkyl.

In some embodiments of Formula IIIb, R¹⁶ is —CH₂OH.

In some embodiments of Formula IIIb, R¹⁶ is —CH₂N(R^(17b))₂.

In some embodiments of Formula IIIb, R¹⁶ is —CH₂NH₂.

In some embodiments of Formula IIIb, R¹⁶ is —CH₂NHMe.

In some embodiments of Formula IIIb, R¹⁶ is —CH₂NMe₂.

In some embodiments of Formula IIIb, R¹⁶ is —CH₂NHEt.

In some embodiments of Formula IIIb, R¹⁶ is —CH₂N(Me)(Et).

In some embodiments of Formula IIIb, R¹⁶ is —CH₂NEt₂.

Some additional embodiments of Formula III include compounds of Formula(IIIc):

or salts, pharmaceutically acceptable salts, or prodrugs thereof.

In some embodiments of Formula IIIc, Ring E is selected from the groupconsisting of

In some embodiments of Formula IIIc, R¹⁰ is selected from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR¹³, CF₃, and CN.

In some embodiments of Formula IIIc, R¹¹ is selected from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(13b))₂, —C₁₋₃haloalkyl, halide, —OR¹³, CF₃, and CN.

In some embodiments of Formula IIIc, R^(12a) is a substituent attachedto the para position of the phenyl ring and is independently selected ateach occurrence from the group consisting of unsubstituted —C₂₋₆ alkyl,—CH₂OH, —CH₂N(R^(13b))₂, —C₂₋₃ haloalkyl, Cl, I, —OEt, and CN.

In some embodiments of Formula IIIc, R^(12b) is a substituent attachedto the meta position of the phenyl ring and is independently selected ateach occurrence from the group consisting of unsubstituted —C₂₋₆ alkyl,—CH₂OH, —CH₂N(R^(13b))₂, —C₁₋₃ haloalkyl, iodide, —OR^(13a), and CF₃.

In some embodiments of Formula IIIc, R^(12c) is a substituent attachedto the ortho position of the phenyl ring and is independently selectedat each occurrence from the group consisting of unsubstituted —C₂₋₆alkyl, —CH₂OH, —CH₂N(R^(13b))₂, —C₁₋₃ haloalkyl, F, I, —OR^(13a), CF₃,and CN.

In some embodiments of Formula IIIc, R^(12d) is 2-5 substituents, eachattached to Ring E and are independently selected at each occurrencefrom the group consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(13b))₂, —C₁₋₃ haloalkyl, F, Br, I, —OR¹³, CF₃, and CN.

In some embodiments of Formula IIIc, each R¹³ is independently selectedfrom the group consisting of unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl,and CF₃.

In some embodiments of Formula IIIc, each R^(13a) is independentlyselected from the group consisting of unsubstituted —C₂₋₆ alkyl, —C₁₋₃haloalkyl, and CF₃.

In some embodiments of Formula IIIc, each R^(13b) is independentlyselected from the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula IIIc, q is an integer of 1 to 5.

In some embodiments of Formula IIIc, R^(12a), R^(12b), R^(12c), R^(12d)and/or R^(13a) is —C₂₋₆ alkyl.

In some embodiments of Formula IIIc, R^(12a), R^(12b), R^(12c), R^(12d)and/or R^(13a) is —C₂₋₅ alkyl.

In some embodiments of Formula IIIc, R^(12a), R^(12b), R^(12c), R^(12d)and/or R^(13a) is —C₂₄ alkyl.

In some embodiments of Formula IIIc, R^(12a), R^(12b), R^(12c), R^(12d)and/or R^(13a) is —C₃₋₆ alkyl.

In some embodiments of Formula IIIc, R^(12a), R^(12b), R^(12c), R^(12d)and/or R^(13a) is —C₄₋₆ alkyl.

In some embodiments of Formula IIIc, R^(12d) and/or R^(13a) is Me.

In some embodiments of Formula IIIc, R^(12b), R^(12c), R^(12d) and/orR^(13a) is CF₃.

In some embodiments of Formula IIIc, R^(12c) and/or R^(12d) is F.

In some embodiments of Formula IIIc, R^(12a) is Cl.

In some embodiments of Formula IIIc, R^(12a), R^(12c), and/or R^(12d) isCN.

In some embodiments of Formula IIIc, R^(12a), R^(12b), R^(12c), and/orR^(12d) is —CH₂OH.

In some embodiments of Formula IIIc, R^(12a), R^(12b), R^(12c), and/orR^(12d) is —CH₂N(R^(13b))₂.

In some embodiments of Formula IIIc, R^(12a), R^(12b), R^(12c), and/orR^(12d) is —CH₂NH₂.

In some embodiments of Formula IIIc, R^(12a), R^(12b), R^(12c), and/orR^(12d) is —CH₂NHMe.

In some embodiments of Formula IIIc, R^(12a), R^(12b), R^(12c), and/orR^(12d) is —CH₂NMe₂.

In some embodiments of Formula IIIc, R^(12a), R^(12b), R^(12c), and/orR^(12d) is —CH₂NHEt.

In some embodiments of Formula IIIc, R^(12a), R^(12b), R^(12c), and/orR^(12d) is —CH₂N(Me)(Et).

In some embodiments of Formula IIIa and/or IIIc, R¹¹ is —CH₂NEt₂.

Some additional embodiments of Formula III include compounds of Formula(IIId):

or salts, pharmaceutically acceptable salts, or prodrugs thereof

In some embodiments of Formula IIId, R¹⁴ is selected from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, and CF₃.

In some embodiments of Formula IIId, R¹⁵ is selected from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, and CF₃.

In some embodiments of Formula IIId, each R¹⁶ is a substituent attachedto the phenyl ring and is independently selected at each occurrence fromthe group consisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH,—CH₂N(R^(17b))₂, —C₁₋₃ haloalkyl, halide, —OR^(17a), CF₃, and CN.

In some embodiments of Formula IIId, each R^(17a) is independentlyselected from the group consisting of unsubstituted —C₃₋₆ alkyl, —C₁₋₃haloalkyl, and CF₃.

In some embodiments of Formula IIId, each R^(17b) is independentlyselected from the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula IIId, q is an integer of 1 to 5.

In some embodiments of Formula IIId, R¹⁷ is —C₃₋₆ alkyl.

In some embodiments of Formula IIId, R¹⁷ is —C₄₋₆ alkyl.

In some embodiments of Formula IIId, R¹⁷ is —C₃₋₅ alkyl.

In some embodiments of Formula IIId, R¹⁶ is —CH₂OH.

In some embodiments of Formula IIId, R¹⁶ is —CH₂N(R^(17b))₂.

In some embodiments of Formula IIId, R¹⁶ is —CH₂NH₂.

In some embodiments of Formula IIId, R¹⁶ is —CH₂NHMe.

In some embodiments of Formula IIId, R¹⁶ is —CH₂NMe₂.

In some embodiments of Formula IIId, R¹⁶ is —CH₂NHEt.

In some embodiments of Formula IIId, R¹⁶ is —CH₂N(Me)(Et).

In some embodiments of Formula IIId, R¹⁶ is —CH₂NEt₂.

Some embodiments of the present disclosure include compounds of Formula(IV):

or salts, pharmaceutically acceptable salts, or prodrugs thereof.

In some embodiments of Formula IV, Ring F is

In some embodiments of Formula IV, Ring G is selected from the groupconsisting of

and a 5-6 membered heteroarylR^(19d), wherein a carbon atom on the ringis attached to the carbonyl carbon.

In some embodiments of Formula IV, each R¹⁸ is a substituent attached toRing F and is independently selected at each occurrence from the groupconsisting of H, —C₁₋₃ haloalkyl, halide, —OR²⁰, CF₃, and CN.

In some embodiments of Formula IV, R^(19a) is a substituent attached tothe para position of phenyl and is selected from the group consisting ofH, unsubstituted C₂₋₆ alkyl, —CH₂OH, —CH₂N(R²¹)₂, —C₁₋₃ haloalkyl, F,Br, I, —OR²⁰, CF₃, and CN.

In some embodiments of Formula IV, R^(19b) is a substituent attached tothe meta or ortho position of phenyl and is selected from the groupconsisting of H, unsubstituted —C₂₋₆ alkyl, —CH₂OH, —CH₂N(R²¹)₂, —C₁₋₃haloalkyl, halide, —OR²⁰, CF₃, and CN.

In some embodiments of Formula IV, R^(19c) is 2-5 substituents, eachattached to the phenyl and are independently selected at each occurrencefrom the group consisting of H, —CH₂OH, —CH₂N(R²¹)₂, —C₁₋₃ haloalkyl,halide, —OR²⁰, CF₃, and CN.

In some embodiments of Formula IV, R^(19d) is 1-4 substituents, eachattached to the heteroaryl ring and is independently selected at eachoccurrence from the group consisting of H, —CH₂OH, —CH₂N(R²¹)₂, —C₁₋₃haloalkyl, halide, —OR²⁰, CF₃, and CN.

In some embodiments of Formula IV, each R²⁰ is independently selectedfrom the group consisting of H, unsubstituted —C₃₋₆ alkyl, —C₁₋₃haloalkyl, and CF₃.

In some embodiments of Formula IV, each R²¹ is independently selectedfrom the group consisting of H and unsubstituted —C₁₋₃ alkyl.

In some embodiments of Formula IV, p is an integer of 1 to 13.

In some embodiments of Formula IV, r is an integer of 1 to 5.

In some embodiments of Formula IV,

is selected from the group consisting of:

In some embodiments of Formula IV,

is selected from the group consisting of:

In some embodiments of Formula IV, R^(19b), R^(19c), and/or R^(19d) isselected from the group consisting of H, F, Cl, Me, OMe, CF₃, and CN.

In some embodiments of Formula IV, R^(19a), R^(19b), R^(19c), and/orR^(19d) is H.

In some embodiments of Formula IV, R^(19b), R^(19c), and/or R^(19d) is ahalide.

In some embodiments of Formula IV, R^(19a), R^(19b), R^(19c), and/orR^(19d) is F.

In some embodiments of Formula IV, R^(19b), R^(19c), and/or R^(19d) isCl.

In some embodiments of Formula IV, R^(19a), R^(19b), R^(19c), and/orR^(19d) is Me.

In some embodiments of Formula IV, R^(19a), R^(19b), R^(19c), and/orR^(19d) is OH.

In some embodiments of Formula IV, R^(19a), R^(19b), R^(19c), and/orR^(19d) is OMe.

In some embodiments of Formula IV, R^(19a), R^(19b), R^(19c), and/orR^(19d) is CF₃.

In some embodiments of Formula IV, R^(19a), R^(19b), R^(19c), and/orR^(19d) is CN.

In some embodiments of Formula IV, R^(19d) is 2 substituents and bothare F.

In some embodiments of Formula IV, R^(19d) is 2 substituents and bothare Me.

In some embodiments of Formula IV, R^(19d) is 2 substituents and bothare CF₃.

In some embodiments of Formula IV, R^(19d) is 2 substituents and bothare OMe.

In some embodiments of Formula IV, R^(19d) is 2 substituents and are Fand Me.

In some embodiments of Formula IV, R^(19d) is 2 substituents and are Fand CF₃.

In some embodiments of Formula IV, R^(19d) is 2 substituents and are Fand OMe.

In some embodiments of Formula IV, R^(19d) is 2 substituents and bothare CN.

In some embodiments of Formula IV, R^(19d) is 2 substituents and are Fand CN.

In some embodiments of Formula IV, R^(19d) is 2 substituents and are Fand Cl.

In some embodiments of Formula IV, R^(19a), R^(19b), R^(19c), and/orR^(19d) is —C₁₋₂ alkyl.

In some embodiments of Formula IV, R^(19a), R^(19b), R^(19c), and/orR^(19d) is —C₁₋₃ alkyl.

In some embodiments of Formula IV, R^(19a), R^(19b), R^(19c), and/orR^(19d) is —C₁₋₄ alkyl.

In some embodiments of Formula IV, R^(19a), R^(19b), R^(19c), and/orR^(19d) is —C₁₋₅ alkyl.

In some embodiments of Formula IV, R^(19a), R^(19b), R^(19c), and/orR^(19d) is —C₁₋₆ alkyl.

In some embodiments of Formula IV, R^(19a), R^(19b), R^(19c), and/orR^(19d) is C₂₋₆ alkyl.

In some embodiments of Formula IV, R^(19a), R^(19b), R^(19c), and/orR^(19d) is C₃₋₆ alkyl.

In some embodiments of Formula IV, R^(19a), R^(19b), R^(19c), and/orR^(19d) is C₄₋₆ alkyl.

In some embodiments of Formula IV, R^(19a), R^(19b), R^(19c), and/orR^(19d) is C₂₋₅ alkyl.

In some embodiments of Formula IV, R^(19a), R^(19b), R^(19c), and/orR^(19d) is C₃₋₅ alkyl.

In some embodiments of Formula IV, R^(19a), R^(19b), R^(19c), and/orR^(19d) is —CH₂OH.

In some embodiments of Formula IV, R^(19a), R^(19b), R^(19c), and/orR^(19d) is —CH₂N(R^(13b))₂.

In some embodiments of Formula IV, R^(19a), R^(19b), R^(19c), and/orR^(19d) is —CH₂NH₂.

In some embodiments of Formula IV, R^(19a), R^(19b), R^(19c), and/orR^(19d) is —CH₂NHMe.

In some embodiments of Formula IV, R^(19a), R^(19b), R^(19c), and/orR^(19d) is —CH₂NMe₂.

In some embodiments of Formula IV, R^(19a), R^(19b), R^(19c), and/orR^(19d) is —CH₂NHEt.

In some embodiments of Formula IV, R^(19a), R^(19b), R^(19c), and/orR^(19d) is —CH₂N(Me)(Et).

In some embodiments of Formula IV, R^(19a), R^(19b), R^(19c), and/orR^(19d) is —CH₂NEt₂.

In some embodiments of Formula IV,

is selected from the group consisting of:

wherein the carbonyl carbon of Formula IV can form a bond with any

In some embodiments of Formula IV, unsubstituted carbon on the Ring G.

is selected from the group consisting of:

In some embodiments of Formula IV,

is selected from the group consisting of:

Illustrative compounds of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih,Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, andIV are shown in Table 1.

TABLE 1

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2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

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Administration and Pharmaceutical Compositions

Some embodiments include pharmaceutical compositions comprising: (a) atherapeutically effective amount of a compound provided herein, or itscorresponding enantiomer, diastereoisomer or tautomer, orpharmaceutically acceptable salt thereof; and (b) a pharmaceuticallyacceptable carrier.

The compounds provided herein may also be useful in combination(administered together or sequentially) with other known agents.

Non-limiting examples of diseases which can be treated with acombination of a compound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih,Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId,and/or IV and other known agents are alopecia, idiopathic pulmonaryfibrosis, sensorineural hearing loss (SNHL), spinal cord injury,osteoporosis, Alzheimer's disease, macular degeneration, and retinitispigmentosa.

In some embodiments, alopecia can be treated with a combination of acompound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb,IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV and one ormore of Minoxidil (Rogaine) and Finasteride (Propecia).

In some embodiments, a composition containing a compound of Formula I,Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf,III, IIIa, IIIb, IIIc, IIId, and/or IV could be applied after adermatologic surgeon transplants micrografts of skin containing hairfollicles. In some embodiments, the micrografts are transplanted fromone area of the scalp to another.

In some embodiments, a composition containing a compound of Formula I,Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf,III, IIIa, IIIb, IIIc, IIId, and/or IV could be applied after scalpreduction, which is the surgical removal of scalp skin without hair, orafter flap surgery, which involves moving the scalp with hair to anadjacent area that is lacking hair.

In some embodiments, idiopathic pulmonary fibrosis can be treated with acombination of a compound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih,Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId,and/or IV and one or more of: pirfenidone (Esbriet), prednisone,azathioprine, N-acetylcysteine, interferon gamma-1b, bosentan,Nintedanib (BIBF 1120), QAX576, and an anti-inflammatory agent such as acorticosteroids.

In some embodiments, sensorineural hearing loss (SNHL) can be treatedwith a combination of a compound of Formula I, Ia, Ib, Ic, Id, Ie, If,Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc,IIId, and/or IV and one or more of the following therapies: (a) haircell regeneration using stem cell and gene therapy; (b) with hearingaids; (c) with cochlear implants; (d) with idebenone or combined withvitamin E; (e) with an anti-inflammatory agent such as a corticosteroid;or (f) with high doses of vitamins A, C, and E, and magnesium.

In some embodiments, spinal cord injury can be treated with acombination of a compound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih,Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId,and/or IV and one or more of the following therapies: (a) surgery toremove any bone fragments from the spinal canal and to stabilize thespine; (b) an anti-inflammatory agent such as a corticosteroid, such asmethylprednisolone; (c) with physical therapy and/or mechanical devices;(d) with the promotion of axonal sprouting/regeneration byco-administration of hydrogels or self-assembling nanofibers; (e) byco-administration of carbon nanotubes; or (f) by co-administration ofpoly-lactic acid microfibers.

In some instances, a compound according to Formula I, Ia, Ib, Ic, Id,Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb,IIIc, IIId, and/or IV is administered in combination with one or moresecond therapeutic agents, e.g., therapeutic agents useful in thetreatment of bone disorders or conditions described herein. For example,certain second therapeutic agents can promote tissue growth orinfiltration, such as growth factors. Exemplary growth factors include,without limitation, epidermal growth factor (EGF), vascular endothelialgrowth factor (VEGF), fibroblast growth factor (FGF), platelet-derivedgrowth factor (PDGF), transforming growth factors (TGFs), parathyroidhormone (PTH), leukemia inhibitory factor (LIF), and insulin-like growthfactors (IGFs). Other second therapeutic agents can promote bone growth,such as bone morphogenetic proteins (U.S. Pat. No. 4,761,471; PCT Pub.WO 90/11366), osteogenin [Sampath, et al., Proc. Natl. Acad. Sci. USA(1987), 84(20), 7109-7113], NaF [Tencer, et al., Journal of BiomedicalMaterials Research (1989), 23(6), 571-589], and peptide sequences suchas IKVAV [Tashiro, et al., The Journal of Biological Chemistry (1989),264(27), 16174-16182].

In some embodiments, osteoporosis can be treated with a combination of acompound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb,IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV and one ormore of: Alendronate (Fosamax), Risedronate (Actonel, Atelvia),Ibandronate (Boniva), Zoledronic acid (Reclast, Zometa), Teriparatide,Raloxifene, Denosumab, and strontium ranelate.

In some embodiments, osteoporosis can be treated with a combination of acompound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb,IIc, IId, IIe, III, IIIa, IIIb, IIIc, IIId, and/or IV and one or more ofthe following therapies: (a) systemic hormone therapy (e.g., estrogen);(b) estrogen in conjunction with progesterone and/or progestin; and (c)with exercise and/or nutritional changes (e.g., an increase in theintake of sources of calcium and vitamin D, and/or an increase in theintake of sources of vitamin D and/or vitamin K).

In some embodiments, Alzheimer's disease can be treated with acombination of a compound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih,Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId,and/or IV and one or more of: cholinesterase inhibitors such asDonepezil (Aricept), Glutamine (Razadyne), and Rivastigmine (Exelon);memantine; or with production blockers to reduce the amount ofbeta-amyloid formed in the brain.

In some embodiments, a composition containing a compound of Formula I,Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf,III, IIIa, IIIb, IIIc, IIId, and/or IV could be combined withimmunization strategies to prevent beta-amyloid from clumping intoplaques and help the body clear it from the brain.

In some embodiments, macular degeneration can be treated with acombination of a compound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih,Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId,and/or IV and one or more of: Bevacizumab (Avastin), Ranibizumab(Lucentis), Pegaptanib (Macugen), or Aflibercept (Eylea).

In some embodiments, macular degeneration can be treated with acombination of a compound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih,Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId,and/or IV and one or more of the following therapies: (a) photodynamictherapy (PDT) (in some cases in combination with a compound likeverteporfin (Visudyne)); (b) laser treatment; or (c) increased vitaminintake of antioxidant vitamins and/or zinc. The following vitamins aresuggested: vitamin C, vitamin E, β-carotene (often as vitamin A), zinc(as zinc oxide), and copper.

In some embodiments, retinitis pigmentosa can be treated with acombination of a compound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih,Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId,and/or IV and one or more of the following active agents or therapies:(a) vitamin A palmitate; (b) the Argus II retinal implant; (c) UF-021(Ocuseva); (d) stem cell and/or gene therapy; or (e) Pikachurin.

Administration of the compounds disclosed herein or the pharmaceuticallyacceptable salts thereof can be via any of the accepted modes ofadministration for agents that serve similar utilities including, butnot limited to, orally, subcutaneously, intravenously, intralymphatic,intranasally, topically, transdermally, intraperitoneally,intramuscularly, intrapulmonarilly, vaginally, rectally, ontologically,neuro-otologically, intraocularly, subconjuctivally, via anterior eyechamber injection, intravitreally, intraperitoneally, intrathecally,intracystically, intrapleurally, via wound irrigation, intrabuccally,intra-abdominally, intra-articularly, intra-aurally, intrabronchially,intracapsularly, intrameningeally, via inhalation, via endotracheal orendobronchial instillation, via direct instillation into pulmonarycavities, intraspinally, intrasynovially, intrathoracically, viathoracostomy irrigation, epidurally, intratympanically,intracisternally, intravascularly, intraventricularly, intraosseously,via irrigation of infected bone, or via application as part of anyadmixture with a prosthetic device. In some embodiments, a compound isadministered orally or parenterally.

Compounds provided herein intended for pharmaceutical use may beadministered as crystalline or amorphous products. Pharmaceuticallyacceptable compositions may include solid, semi-solid, liquid,solutions, colloidal, liposomes, emulsions, suspensions, complexes,coacervates and aerosols. Dosage forms, such as, e.g., tablets,capsules, powders, liquids, suspensions, suppositories, aerosols,implants, controlled release or the like, are provided herein. Thedosage forms may be obtained, for example, as solid plugs, powders, orfilms by methods such as precipitation, crystallization, milling,grinding, supercritical fluid processing, coacervation, complexcoacervation, encapsulation, emulsification, complexation, freezedrying, spray drying, or evaporative drying. Microwave or radiofrequency drying may also be used. The compounds can also beadministered in sustained or controlled release dosage forms, includingdepot injections, osmotic pumps, pills (tablets and/or capsules),transdermal (including electrotransport) patches, implants and the like,for prolonged and/or timed, pulsed administration at a predeterminedrate.

Controlled-release systems can include a component selected from thegroup consisting of immediate release component(s), pulsatile releasecomponent(s), delayed release component(s), sustained releasecomponent(s), and combinations thereof. Systems may be in, for example,the form of a matrix, reservoir/membrane, osmotic pump, or hybridsthereof. In some embodiments, a controlled-release system can includecompounds entrapped in or otherwise incorporated into or coupled withpolymer carriers or polymeric devices, such as micelles, nanoparticles,microspheres, hydrogels, and other types of polymer carriers or devices.In some embodiments, the controlled-release system delivers a compoundprovided herein at a controlled rate for an extended period of time. Inanother embodiment, the controlled-release system localizes the actionof a compound by spatial placement near where the compound is needed. Inanother embodiment, the controlled release system includes targeteddelivery of a compound to a particular cell type.

The compounds can be administered either alone or more typically incombination with a conventional pharmaceutical carrier, excipient,diluent, or the like. The term “excipient” is used herein to describeany ingredient other than the compound(s) provided herein.Pharmaceutically acceptable excipients include, but are not limited to,ion exchangers; alumina; aluminum stearate; lecithin; self-emulsifyingdrug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol1000 succinate; surfactants used in pharmaceutical dosage forms such asTweens, poloxamers or other similar polymeric delivery matrices; serumproteins, such as human serum albumin; buffer substances such asphosphates, tris, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethyl cellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, andwool fat. Cyclodextrins such as α-, β, and γ-cyclodextrin, or chemicallymodified derivatives such as hydroxyalkylcyclodextrins, including 2- and3-hydroxypropyl-b-cyclodextrins, or other solubilized derivatives canalso be used to enhance delivery of compounds described herein. Dosageforms or compositions containing a compound as described herein in therange of 0.005% to 100% with the balance made up from non-toxic carriermay be prepared. The contemplated compositions may contain 0.001%-100%active ingredient, in one embodiment 0.1-95%, in another embodiment75-85%, in a further embodiment 20-80%. Actual methods of preparing suchdosage forms are known, or will be apparent, to those skilled in thisart; for example, see Remington: The Science and Practice of Pharmacy,22^(nd) (Pharmaceutical Press, London, UK. 2012).

In one embodiment, the compositions can take the form of a unit dosageform such as a pill or tablet and thus the composition may contain,along with the active ingredient, a diluent such as lactose, sucrose,dicalcium phosphate, or the like; a lubricant such as magnesium stearateor the like; and a binder such as starch, gum acacia,polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or thelike. In another solid dosage form, a powder, marume, solution orsuspension (e.g., in propylene carbonate, vegetable oils, PEG's,poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin orcellulose base capsule) or as a dry powder. Unit dosage forms in whichthe two active ingredients are physically separated are alsocontemplated; e.g., capsules with granules (or tablets in a capsule) ofeach drug; two-layer tablets; two-compartment gel caps, etc. Entericcoated or delayed release oral dosage forms are also contemplated.

In another preferred embodiment, compositions described herein are usedas compound-eluting compositions (e.g., controlled release) for amedical device including, but not limited to a temporary or permanentimplant, sponge, polymer, or gel.

The implant according to an embodiment of the disclosure is anorthopedic implant including, but not limited to (i) a hip joint, (ii)screws, cannulated screws, nails, meshs, cages, wires, pins,intramedullary nails, rods, posts, anchors, and plates intended to joinor attach bone fragments, pieces, or parts with each other, (iii)external skeletal fixators such as monolateral, multiplanar or hybridfixators, (iv) implants intended for treatment of degenerativeinstabilities, fractures, tumors, and deformities in respect of thespine, (v) cranio-maxillofacial implants intended for treatment offractures, reconstruction, and correction of deformities, of mandible,mid-face, or skull, (vi) surgical stents, collagen stents,intramedullary bone stents, (vii) anterior cruciate ligament (ACL)and/or posterior cruciate ligament (PCL) Reconstruction Systems, and(viii) dental implants.

Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing, etc. a compound as provided hereinand optional pharmaceutical adjuvants in a carrier (e.g., water, saline,aqueous dextrose, glycerol, glycols, ethanol or the like) to form asolution, colloid, liposome, emulsion, complexes (including inclusioncomplexes), coacervate, or suspension. If desired, the pharmaceuticalcomposition can also contain auxiliary substances such as wettingagents, emulsifying agents, co-solvents, solubilizing agents, pHbuffering agents, and the like (e.g., sodium acetate, sodium citrate,cyclodextrins and derivatives, sorbitan monolaurate, triethanolamineacetate, triethanolamine oleate, and the like).

In some embodiments, the unit dosage of compounds of Formula I, Ia, Ib,Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa,IIIb, IIIc, IIId, and/or IV for oral systemic delivery is about 0.25mg/Kg to about 50 mg/Kg.

In some embodiments, the unit dosage of compounds of Formula I, Ia, Ib,Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa,IIIb, IIIc, IIId, and/or IV for systemic delivery is about 0.25 mg/Kg toabout 20 mg/Kg.

In some embodiments, the unit dosage of compounds of Formula I, Ia, Ib,Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa,IIIb, IIIc, IIId, and/or IV for local delivery is about 0.050 μg/Kg toabout 50 μg/Kg.

In some embodiments, the unit dosage of compounds of Formula I, Ia, Ib,Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa,IIIb, IIIc, IIId, and/or IV for topical delivery is about 0.1 μg/cm² toabout 20 μg/cm².

In some embodiments, the unit dosage of compounds of Formula I, Ia, Ib,Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa,IIIb, IIIc, IIId, and/or IV is about 1.0 μg/eye to about 1 mg/eye.

In some embodiments, the unit dosage of compounds of Formula I, Ia, Ib,Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa,IIIb, IIIc, IIId, and/or IV loaded into a compound-eluting implant isabout 0.1 μg/Kg to about 1 mg/Kg.

In some embodiments, the unit dosage of compounds of Formula I, Ia, Ib,Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa,IIIb, IIIc, IIId, and/or IV for pulmonary delivery is about 1 μg/dose toabout 15 mg/dose.

In some embodiments, the unit dosage of compounds of Formula I, Ia, Ib,Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa,IIIb, IIIc, IIId, and/or IV for parenteral administration is about 0.05mg/Kg to about 15 mg/Kg.

In some embodiments, the unit dosage of compounds of Formula I, Ia, Ib,Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa,IIIb, IIIc, IIId, and/or IV is about 2.0 mg/Kg to about 13 mg/Kg inhumans.

In some embodiments, the unit dosage of compounds of Formula I, Ia, Ib,Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa,IIIb, IIIc, IIId, and/or IV is about 3.0 mg/Kg to about 12 mg/Kg inhumans.

In some embodiments, the unit dosage of compounds of Formula I, Ia, Ib,Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa,IIIb, IIIc, IIId, and/or IV is about 4.0 mg/Kg to about 11 mg/Kg inhumans.

In some embodiments, the unit dosage of compounds of Formula I, Ia, Ib,Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa,IIIb, IIIc, IIId, and/or IV is about 5.0 mg/Kg to about 10 mg/Kg inhumans.

In some embodiments, the compositions are provided in unit dosage formssuitable for single administration.

In some embodiments, the compositions are provided in unit dosage formssuitable for twice a day administration.

In some embodiments, the compositions are provided in unit dosage formssuitable for three times a day administration.

Injectables can be prepared in conventional forms, either as liquidsolutions, colloids, liposomes, complexes (like inclusion complexes),coacervate, or suspensions, as emulsions, or in solid forms suitable forreconstitution in liquid prior to injection. The percentage of acompound provided herein contained in such parenteral compositions isdependent on the specific disorder being treated, the activity of thecompound, and the needs of the patient. However, percentages ofingredient compound of about 0.01% to about 10% in solution may be used,and could be higher if the composition is a concentrated solid orsuspension, which could be subsequently diluted.

In some embodiments, a composition can comprise about 0.01 to about 10%of the compound in solution.

In some embodiments, the composition will comprise about 0.01 to about5% of the compound in solution.

In some embodiments, the composition will comprise about 0.01 to about4% of the compound in solution.

In some embodiments, the composition will comprise about 0.05 to about3% of the compound in solution.

In some embodiments, the composition will comprise about 0.02 to about2% of the compound in solution.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period ofabout 1 to about 96 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period ofabout 1 to about 72 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period ofabout 1 to about 48 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period ofabout 1 to about 24 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period ofabout 1 to about 12 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period ofabout 1 to about 6 hours.

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 1.5 mg/m² to about 300mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 1.5 mg/m² to about 200mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 1.5 mg/m² to about 100mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 1.0 mg/m² to about 50mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 50 mg/m² to about 200mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 75 mg/m² to about 175mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 100 mg/m² to about 150mg/m².

It is to be noted that concentrations and dosage values may also varydepending on the specific compound and the severity of the condition tobe alleviated. It is to be further understood that for any particularpatient, specific dosage regimens can be adjusted over time according tothe individual need and the professional judgment of the personadministering or supervising the administration of the compositions, andthat the concentration ranges set forth herein are exemplary only andare not intended to limit the scope or practice of the claimedcompositions.

In one embodiment, the compositions can be administered to therespiratory tract (including nasal and pulmonary) e.g., through anebulizer, metered-dose inhalers, atomizer, mister, aerosol, dry powderinhaler, insufflator, liquid instillation, or other suitable device ortechnique.

In some embodiments, aerosols intended for delivery to the nasal mucosaare provided for inhalation through the nose. For delivery to the nasalcavities, inhaled particle sizes of about 5 to about 100 microns can beused, for example, particle sizes of about 10 to about 60 microns. Fornasal delivery, a larger inhaled particle size is can be used. In someembodiments, the larger particles may maximize impaction on the nasalmucosa or minimize or prevent pulmonary deposition of the administeredformulation. In some embodiments, aerosols intended for delivery to thelungs are provided for inhalation through the nose or the mouth. Fordelivery to the lung, inhaled aerodynamic particle sizes of about lessthan 10 μm can be used, for example, an aerodynamic particle size ofabout 1 to about 10 microns can be used. Inhaled particles may bedefined as liquid droplets containing dissolved compound, liquiddroplets containing suspended compound particles (in cases where thecompound is insoluble in the suspending medium), dry particles of purecompound, compound incorporated with excipients, liposomes, emulsions,colloidal systems, coacervates, aggregates of compound nanoparticles, ordry particles of a diluent which contain embedded compoundnanoparticles.

In some embodiments, compounds of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig,Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId,and/or IV disclosed herein intended for respiratory delivery (eithersystemic or local) can be administered as aqueous formulations, asnon-aqueous solutions or suspensions, as suspensions or solutions inhalogenated hydrocarbon propellants with or without alcohol, as acolloidal system, as emulsions, coacervates, or as dry powders. Aqueousformulations may be aerosolized by liquid nebulizers employing eitherhydraulic or ultrasonic atomization or by modified micropump systems(like the soft mist inhalers, the Aerodose®, or the AERX® systems).Propellant-based systems may use suitable pressurized metered-doseinhalers (pMDIs). Dry powders may use dry powder inhaler devices (DPIs),which are capable of dispersing the compound substance effectively. Adesired particle size and distribution may be obtained by choosing anappropriate device.

In some embodiments, the compositions of Formula I, Ia, Ib, Ic, Id, Ie,If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc,IIId, and/or IV disclosed herein can be administered to the ear byvarious methods. For example, a round window catheter (e.g., U.S. Pat.Nos. 6,440,102 and 6,648,873) can be used.

Alternatively, formulations can be incorporated into a wick for usebetween the outer and middle ear (e.g., U.S. Pat. No. 6,120,484) orabsorbed to collagen sponge or other solid support (e.g., U.S. Pat. No.4,164,559).

If desired, formulations of the disclosure can be incorporated into agel formulation (e.g., U.S. Pat. Nos. 4,474,752 and 6,911,211).

In some embodiments, compounds of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig,Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId,and/or IV disclosed herein intended for delivery to the ear can beadministered via an implanted pump and delivery system (e.g., through aneedle directly into the middle or inner ear (cochlea) or through acochlear implant stylet electrode channel or alternative preparedcompound delivery channel such as but not limited to a needle throughtemporal bone into the cochlea).

Other options include delivery via a pump through a thin film coatedonto a multichannel electrode or electrode with a specially imbeddedcompound delivery channel (pathways) carved into the thin film for thispurpose. In other embodiments, a compound provided herein can bedelivered from the reservoir of an external or internal implantedpumping system.

Formulations of the disclosure also can be administered to the ear byintratympanic injection into the middle ear, inner ear, or cochlea(e.g., U.S. Pat. No. 6,377,849 and Ser. No. 11/337,815).

Intratympanic injection of therapeutic agents is the technique ofinjecting a therapeutic agent behind the tympanic membrane into themiddle and/or inner ear. In one embodiment, the formulations describedherein are administered directly onto the round window membrane viatranstympanic injection. In another embodiment, the ion channelmodulating agent auris-acceptable formulations described herein areadministered onto the round window membrane via a non-transtympanicapproach to the inner ear. In additional embodiments, the formulationsdescribed herein are administered onto the round window membrane via asurgical approach to the round window membrane comprising modificationof the crista fenestrae cochleae.

In some embodiments, the compounds of Formula I, Ia, Ib, Ic, Id, Ie, If,Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc,IIId, and/or IV are formulated into rectal compositions such as enemas,rectal gels, rectal foams, rectal aerosols, suppositories, jellysuppositories, or retention enemas, containing conventional suppositorybases such as cocoa butter or other glycerides, as well as syntheticpolymers such as polyvinylpyrrolidone, PEG (like PEG ointments), and thelike.

Suppositories for rectal administration of the compound (either as asolution, colloid, suspension, or a complex) can be prepared by mixingthe compound with a suitable non-irritating excipient that is solid atordinary temperatures but liquid at the rectal temperature and willtherefore melt or erode/dissolve in the rectum and release the compound.Such materials include cocoa butter, glycerinated gelatin, hydrogenatedvegetable oils, poloxamers, mixtures of polyethylene glycols of variousmolecular weights and fatty acid esters of polyethylene glycol.

Solid compositions can be provided in various different types of dosageforms, depending on the physicochemical properties of the compound, thedesired dissolution rate, cost considerations, and other criteria. Inone of the embodiments, the solid composition is a single unit. Thisimplies that one unit dose of the compound is comprised in a single,physically shaped solid form or article. In other words, the solidcomposition is coherent, which is in contrast to a multiple unit dosageform, in which the units are incoherent.

Examples of single units which may be used as dosage forms for the solidcomposition include tablets, such as compressed tablets, film-likeunits, foil-like units, wafers, lyophilized matrix units, and the like.In some embodiments, the solid composition is a highly porouslyophilized form. Such lyophilizates, sometimes also called wafers orlyophilized tablets, can be useful for their rapid disintegration, whichcan allow for the rapid dissolution of the compound.

In some embodiments, the solid composition may also be formed as amultiple unit dosage form as defined above. Examples of multiple unitsare powders, granules, microparticles, pellets, mini-tablets, beads,lyophilized powders, and the like. In one embodiment, the solidcomposition is a lyophilized powder. Such a dispersed lyophilized systemcomprises a multitude of powder particles, and due to the lyophilizationprocess used in the formation of the powder, each particle has anirregular, porous microstructure through which the powder is capable ofabsorbing water very rapidly, resulting in quick dissolution.Effervescent compositions are also contemplated to aid the quickdispersion and absorption of the compound.

Another type of multiparticulate system which is also capable ofachieving rapid compound dissolution is that of powders, granules, orpellets from water-soluble excipients which are coated with thecompound, so that the compound is located at the outer surface of theindividual particles. In this type of system, a water-soluble lowmolecular weight excipient can be useful for preparing the cores of suchcoated particles, which can be subsequently coated with a coatingcomposition comprising the compound and, in some cases, one or moreadditional excipients, such as a binder, a pore former, a saccharide, asugar alcohol, a film-forming polymer, a plasticizer, or otherexcipients used in pharmaceutical coating compositions.

Also provided herein are kits. Typically, a kit includes one or morecompounds or compositions as described herein. In certain embodiments, akit can include one or more delivery systems, e.g., for delivering oradministering a compound as provided herein, and directions for use ofthe kit (e.g., instructions for treating a patient). In anotherembodiment, the kit can include a compound or composition as describedherein and a label that indicates that the contents are to beadministered to a patient with one or more of osteoporosis andosteoarthropathy; osteogenesis imperfecta, bone defects, bone fractures,periodontal disease, otosclerosis, wound healing, craniofacial defects,oncolytic bone disease, traumatic brain injuries related to thedifferentiation and development of the central nervous system,comprising Parkinson's disease, strokes, ischemic cerebral disease,epilepsy, Alzheimer's disease, depression, bipolar disorder,schizophrenia; otic disorders like cochlear hair cell loss; eye diseasesincluding, but not limited to, wet age-related macular degeneration, dryage-related macular degeneration, geographic atrophy, diabeticretinopathy, diabetic macular edema, retinal detachment, retinaldegeneration, retinal vein occlusion, retinopathy of prematurity,retinitis pigmentosa, retinopathies, Leber congenital amaurosis andglaucoma, and diseases related to differentiation and growth of stemcell, comprising hair loss, hematopoiesis related diseases, tissueregeneration related diseases, and other diseases associated withabnormalities in development, stem cell differentiation and cellproliferation.

In some embodiments, a compound-eluting coating or a controlled releasesystem comprising a compound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig,Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId,and/or IV, or a pharmaceutically acceptable salt thereof, is providedherein.

In some embodiments, a medical device comprising a compound of FormulaI, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf,III, IIIa, IIIb, IIIc, IIId, and/or IV, or a pharmaceutically acceptablesalt thereof, is provided herein.

In some embodiments, an implant, sponge, polymer, ointment, cream or gelcomposition suitable for in vivo use comprising a compound of Formula I,Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf,III, IIIa, IIIb, IIIc, IIId, and/or IV, or a pharmaceutically acceptablesalt thereof, is provided herein.

Methods of Treatment

The compounds and compositions provided herein can be used as activatorsof one or more members of the Wnt pathway, including one or more Wntproteins, and thus can be used to treat a variety of disorders anddiseases in which aberrant Wnt signaling is implicated, such asosteoporosis and osteoarthropathy; osteogenesis imperfecta, bonedefects, bone fractures, periodontal disease, otosclerosis, woundhealing, craniofacial defects, oncolytic bone disease, traumatic braininjuries related to the differentiation and development of the centralnervous system, comprising Parkinson's disease, strokes, ischemiccerebral disease, epilepsy, Alzheimer's disease, depression, bipolardisorder, schizophrenia; eye diseases including, but not limited to, wetage-related macular degeneration, dry age-related macular degeneration,geographic atrophy, diabetic retinopathy, diabetic macular edema,retinal detachment, retinal degeneration, retinal vein occlusion,retinopathy of prematurity, retinitis pigmentosa, retinopathies, Lebercongenital amaurosis and glaucoma and diseases related todifferentiation and growth of stem cell, comprising hair loss,hematopoiesis related diseases, tissue regeneration related diseases andother diseases associated with abnormalities in development, stem celldifferentiation and cell proliferation.

With respect to hair loss, the canonical Wnt/β-catenin signaling pathwayhas been linked to hair follicle development and regeneration.Accordingly, the compounds and compositions described herein may be usedtopically to treat hair loss by modulation of the Wnt/β-cateninsignaling pathway.

With respect to neurodegenerative diseases, Wnt/β-catenin signaltransduction system plays a role in the differentiation and developmentof nerve cells for the central nervous system. Consequently, thecompounds and compositions described herein may be used to reactivatelost Wnt signaling function involved in neurodegeneration.

Other neurodegenerative diseases can also be treated with the compoundsand compositions described herein.

More particularly, neurodegenerative diseases that may be treated by thecompound, compositions and methods described herein include, but are notlimited to, the following:

-   -   Parkinson's disease, schizophrenia, Huntington's disease,        amyotrophic lateral sclerosis (Lou Gehrig's disease), primary        lateral sclerosis (PLS), progressive muscular atrophy (PMA),        bipolar disorder, depression, strokes, spinal cord injury,        ischemic cerebral disease, epilepsy, brain damage, and        spinocerebellar ataxia type 1 (SCA1).

With respect to eye diseases, Wnt/β-catenin signal transduction systemis thought to regulate the maintenance of a retinal progenitorpopulation in the ciliary marginal zone (CMZ), and thus can function asa putative stein cell factor in the retina.

Other eye diseases can also be treated with the compounds andcompositions described herein.

More particularly, eye diseases that may be treated by the compound,compositions and methods described herein include, but are not limitedto, the following:

-   -   wet age-related macular degeneration, dry age-related macular        degeneration, geographic atrophy, diabetic retinopathy, diabetic        macular edema, retinal detachment, retinal degeneration, retinal        vein occlusion, retinopathy of prematurity, retinitis        pigmentosa, retinopathies, Leber congenital amaurosis and        glaucoma.

With respect to diseases associated with differentiation and growth ofstem cell, Wnt/β-catenin signaling participates in the self-renewal ofstem cells in many different tissues, including the skin, intestine,brain, and blood. Therefore, the compounds and compositions describedherein may be used to treat disorders and diseases related toabnormalities in development.

In some embodiments, the disclosure provides a method for activating theWnt signaling in order to treat a disorder or disease in a patient, themethod comprising administering to the patient a therapeuticallyeffective amount of a compound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig,Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId,and/or IV, or a pharmaceutically acceptable salt thereof.

In some embodiments, the disorder or disease is neurodegenerativedisease.

In some embodiments, the neurodegenerative disease is Parkinson'sdisease, stroke, spinal cord injury, ischemic cerebral disease,epilepsy, Alzheimer's disease, dementia, depression, bipolar disorder,or schizophrenia.

In some embodiments, the disorder or disease is an eye disease.

In some embodiments, the eye diseases include, but are not limited to,wet age-related macular degeneration, dry age-related maculardegeneration, geographic atrophy, diabetic retinopathy, diabetic macularedema, retinal detachment, retinal degeneration, retinal vein occlusion,retinopathy of prematurity, retinitis pigmentosa, retinopathies, Lebercongenital amaurosis and glaucoma.

In some embodiments, the disorder or disease is related todifferentiation and growth of stem cells such as hair loss,hematopoiesis related diseases, tissue regeneration related diseases andother diseases associated with abnormalities in development, stem celldifferentiation, and cell proliferation.

In some embodiments, the disorder or disease is osteoporosis,osteoarthropathy, osteogenesis imperfecta, bone defects, bone fractures,periodontal disease, otosclerosis, wound healing, mucositis (oral andgastrointestinal), craniofacial defects, and oncolytic bone disease.

In some embodiments, the patient is a mammal. In some embodiments, thepatient is a human.

In some embodiments, a compound of Formula I, Ia, Ib, Ic, Id, Ie, If,Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc,IIId, and/or IV activates one or more proteins in the Wnt pathway.

In some embodiments, a compound of Formula I, Ia, Ib, Ic, Id, Ie, If,Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc,IIId, and/or IV activates signaling induced by one or more Wnt proteins.

In some embodiments, the Wnt proteins are chosen from: WNT1, WNT2,WNT2B, WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A,WNT8B, WNT9A, WNT9B, WNT10A, WNT10B, WNT11, and WNT16.

In some embodiments, a pharmaceutical composition provided hereincomprises a therapeutically effective amount of a compound of Formula I,Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf,III, IIIa, IIIb, IIIc, IIId, and/or IV, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable excipient.

In some embodiments, the pharmaceutical composition comprises atherapeutically effective amount of a compound of Formula I, Ia, Ib, Ic,Id, Ie, If, Ig, Ih, Ii, II, IIa, IIb, IIc, IId, IIe, IIf, III, IIIa,IIIb, IIIc, IIId, and/or IV, wherein the composition is suitable for useas or inclusion in a compound-eluting coating for a medical device.

EXAMPLES Compound Preparation

The starting materials used in preparing the compounds of the disclosureare known, made by known methods, or are commercially available. It willbe apparent to the skilled artisan that methods for preparing precursorsand those compounds functionality related to the compounds providedherein are generally described in the literature. The skilled artisangiven the literature and this disclosure is well equipped to prepare anyof the compounds.

It is recognized that the skilled artisan in the art of organicchemistry can readily carry out manipulations without further direction,that is, it is well within the scope and practice of the skilled artisanto carry out these manipulations. These include reduction of carbonylcompounds to their corresponding alcohols, oxidations, acylations,aromatic substitutions, both electrophilic and nucleophilic,etherifications, esterification and saponification and the like. Thesemanipulations are discussed in standard texts such as March's AdvancedOrganic Chemistry: Reactions, Mechanisms, and Structure 7^(th) Ed., JohnWiley & Sons (2013), Carey and Sundberg, Advanced Organic Chemistry5^(th) Ed., Springer (2007), Comprehensive Organic Transformations: AGuide to Functional Group Transformations, 2^(nd) Ed., John Wiley & Sons(1999) and the like.

The skilled artisan will readily appreciate that certain reactions arebest carried out when other functionality is masked or protected in themolecule, thus avoiding any undesirable side reactions and/or increasingthe yield of the reaction. Often the skilled artisan utilizes protectinggroups to accomplish such increased yields or to avoid the undesiredreactions. These reactions are found in the literature and are also wellwithin the scope of the skilled artisan. Examples of many of thesemanipulations can be found for example in T. Greene and P. WutsProtective Groups in Organic Synthesis, 4^(th) Ed., John Wiley & Sons(2007).

Trademarks used herein are examples only and reflect illustrativematerials used at the time of the invention. The skilled artisan willrecognize that variations in lot, manufacturing processes, and the like,are expected. Hence the examples, and the trademarks used in them arenon-limiting, but are merely an illustration of how a skilled artisanmay choose to perform one or more of the embodiments of the disclosure.

(¹H) nuclear magnetic resonance spectra (NMR) were measured in theindicated solvents on a Bruker NMR spectrometer (Avance™ DRX300, 300 MHzfor ¹H or Avance™ DRX500, 500 MHz for ¹H) or Varian NMR spectrometer(Mercury 400BB, 400 MHz for ¹H). Peak positions are expressed in partsper million (ppm) downfield from tetramethylsilane. The peakmultiplicities are denoted as follows, s, singlet; d, doublet; t,triplet; q, quartet; ABq, AB quartet; quin, quintet; sex, sextet; sep,septet; non, nonet; dd, doublet of doublets; ddd, doublet of doublets ofdoublets; dABq, doublet of AB quartet; dt, doublet of triplets; td,triplet of doublets; dq, doublet of quartets; m, multiplet.

The following abbreviations have the indicated meanings:

-   -   Ac₂O=acetic anhydride    -   BBr₃=boron tribromide    -   BF₃*Et₂O=boron trifluoride ethyl etherate    -   Boc₂O=di-t-butyl dicarbonate    -   B(OiPr)₃=boron tri-isopropoxide    -   brine=saturated aqueous sodium chloride    -   CDCl₃=deuterated chloroform    -   CH(OMe)₃=trimethyl orthoformate    -   Cs₂CO₃=cesium carbonate    -   CuBr₂=copper(II) bromide    -   CuI=copper(I) iodide or cuprous iodide    -   DCM=dichloromethane    -   DMAP=4-dimethylaminopyridine    -   DMF=dimethylforamide    -   DMSO-d₆=deuterated dimethylsulfoxide    -   ESIMS=electron spray mass spectrometry    -   EtOAc=ethyl acetate    -   HCl=hydrochloric acid    -   HOAc=acetic acid    -   HPLC=high-performance liquid chromatography    -   K₂CO₃=potassium carbonate    -   LAH=lithium aluminium hydride    -   m-CPBA=meta-chloroperoxybenzoic acid    -   MeCN=acetonitrile    -   MeOH=methanol    -   MgSO₄=magnesium sulfate    -   NaH=sodium hydride    -   NBS=N-bromosuccinimide    -   NMR=nuclear magnetic resonance    -   Pd(Ph₃)₄=tetrakis(triphenylphosphorus) palladium(0)    -   PE=petroleum ether    -   POCl₃=phosphorus oxychloride    -   TEA=triethylamine    -   THF=tetrahydrofuran    -   TLC=thin layer chromatography

The following example schemes are provided for the guidance of thereader, and collectively represent exemplary methods for making thecompounds provided herein. Furthermore, other methods for preparingcompounds of the disclosure will be readily apparent to the person ofordinary skill in the art in light of the following reaction schemes andexamples. The skilled artisan is thoroughly equipped to prepare thesecompounds by those methods given the literature and this disclosure. Thecompound numberings used in the synthetic schemes depicted below aremeant for those specific schemes only, and should not be construed as orconfused with the same numberings in other sections of the disclosure.Unless otherwise indicated, all variables are as defined above.

General Procedures

Compounds of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV of thepresent disclosure can be prepared as depicted in Scheme 1.

Scheme 1 describes a method for the preparation of unsubstituted1,4-diketones derivatives (V) by the modified Stetter reaction of aMannich base as a vinyl ketone precursor with aldehyde. The Mannich baseis formed by first reacting an aryl methyl ketone (II) withparaformaldehyde and dimethylamine hydrochloride to form the3-dimethylamino-propan-1-one (III). Next, Mannich base (III) was reactedwith various aryl aldehydes (IV) under standard Stetter conditions usinga thiazolium salt as the catalyst yields unsubstituted 1,4-diketonederivatives (V).

Compounds of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV of thepresent disclosure can also be prepared from a methyl ketone and α-bromoketone as depicted in Scheme 2.

Scheme 2 describes a method for the preparation of 1,4-diketonesderivatives (V) by the method of Kel'in and Kulinkovich [Synthesis(1996), (3), 330-2] which is based on the application of magnesiumreagents in the cross-aldol condensation of aryl methyl ketones withα-bromo ketones. An aryl methyl ketone (II) is reacted with asubstituted α-bromo ketone (VI) in the presence of diethylamidomagnesiumbromide and acid followed by treatment with TEA to produce the desired1,4-diketone derivatives (V).

Compounds of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, IIa,IIb, IIc, IId, IIe, IIf, III, IIIa, IIIb, IIIc, IIId, and/or IV of thepresent disclosure can also be prepared from an α-bromo ketone and a1,3-diketone as depicted in Scheme 3.

Scheme 3 describes a method for preparation of unsubstituted1,4-diketones derivatives (V) by first reacting an α-bromo ketone (VI)with a 1,3-diketone in the presence of a mild base to form the triketone(VIII). Next, the triketone (VIII) was debenzoylated with strong base toyield unsubstituted 1,4-diketone derivatives (V).

ILLUSTRATIVE COMPOUND EXAMPLES

Preparation of intermediate (XVI) is depicted below in Scheme 4.

Step 1

To a solution of 3-methoxybenzene-1,2-diol (IX) (15 g, 0.107 mol), andNH₄OAc (0.83 g, 10.7 mmol) in MeCN (500 mL) was added NBS (20 g, 0.112mol) portion wise at room temperature and stirred for an hour. Thereaction mixture was concentrated under vacuum, diluted with EtOAc (300mL), washed with an aqueous solution of 50% NaHSO₃ (200 mL), and brine(200 mL) The EtOAc layer was dried over anhydrous Na₂SO₄, concentratedunder vacuum and purified on a silica gel column (100% DCM) to give3-bromo-6-methoxybenzene-1,2-diol (X) (18 g, 82.2 mmol, 76% yield) as awhite solid. ¹H NMR (CDCl₃, 500 MHz) δ ppm 3.87 (s, 3H), 5.54 (s, 1H),5.60 (s, 1H), 6.42 (d, J=8.78 Hz, 1H), 6.98 (d, J=8.78 Hz, 1H).

Step 2

To a solution of 3-bromo-6-methoxybenzene-1,2-diol (X) (18 g, 82.2mmol), K₂CO₃ (25 g, 0.18 mol) and 1,2-dibromoethane (18.53 g, 0.98.6mmol) in DMF (100 mL) was stirred at 100° C. for 2 h. The reactionmixture was diluted with water (300 mL) and extracted with EtOAc (3×200mL). The combined organic layers were washed with brine (2×100 mL),dried over Na₂SO₄, and concentrated under vacuum. The residue waspurified by column chromatography on silica gel (100% DCM) to produce5-bromo-8-methoxy-2,3-dihydrobenzo[b][1,4]dioxine (XI) (16 g, 65.3 mmol,80% yield) as a white solid. ¹H NMR (CDCl₃, 500 MHz) δ ppm 3.86 (s, 3H),4.35 (dd, J=13.05 Hz, 4.27 Hz, 4H), 6.42 (d, J=8.78 Hz, 1H), 7.03 (d,J=8.78 Hz, 1H).

Step 3

To a solution of 5-bromo-8-methoxy-2,3-dihydrobenzo[b][1,4]dioxine (XI)(16 g, 65.3 mmol) in anhydrous THF (150 mL) was slowly addedn-butyllithium (31.5 mL, 78.4 mmol) dropwise at −78° C. This mixture wasstirred at −78° C. for an hour before adding triisopropylborate (14.8 g,78.4 mmol) dropwise. The reaction was allowed warm to room temperatureand stir overnight before quenching with 2N HCl (100 mL). The mixturewas extracted with EtOAc (2×200 mL). The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄ and concentrated undervacuum. The crude solid was recrystallized with EtOAc/PE to yield8-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-5-ylboronic acid (XII) (12 g,57.1 mmol, 87.5% yield) as a white solid. ¹H NMR (CDCl₃, 500 MHz) δ ppm3.91 (s, 3H), 4.30-4.44 (m, 4H), 5.46 (s, 2H), 6.58 (d, J=8.28 Hz, 1H),7.36 (d, J=8.28 Hz, 1H).

Step 4

To a solution of 8-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-5-ylboronicacid (XII) (12 g, 57.14 mmol) in water (60 mL) and THF (60 mL) was addedNaOH (4 g, 0.1 mmol) at 0° C. and stirred for 20 min. To this clearsolution was added H₂O₂ (19.4 mL, 0.17 mol) dropwise at 0° C. Thereaction mixture was quenched with 50% aqueous NaHSO₃ (100 mL), water(50 mL), and extracted with EtOAc (2×200 mL) The EtOAc layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated to give crude8-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-5-ol (XIII) (12 g, 57.1 mmol,quantitative yield). The crude product was used for the next stepwithout any additional purification.

Step 5

A solution of 8-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-5-ol (XIII),K₂CO₃ (10 g, 70.9 mmol), and MeI (16 g, 0.19 mmol) in DMF (50 mL) wasstirred at 40° C. for 5 h. This reaction mixture was cooled, dilutedwith water (150 mL), and extracted with EtOAc (2×100 mL). The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄,concentrated under vacuum, and purified using a silica gel column (20%EtOAc/PE) to give 5,8-dimethoxy-2,3-dihydrobenzo[b][1,4]dioxine (XIV) (3g, 15.3 mmol, 50% yield) as a yellow oil. ¹H NMR (CDCl₃, 500 MHz) δ ppm3.84 (s, 6H), 4.34 (s, 411), 6.40 (s, 2H).

Step 6

A solution of 5,8-dimethoxy-2,3-dihydrobenzo[b][1,4]dioxine (XIV) (0.75g, 3.82 mmol), ZnCl₂ (3.13 g, 23 mmol) and Ac₂O in CH₃NO₂ (25 mL) wasstirred at 50° C. for 1 h. The reaction mixture was cooled, diluted withEtOAc (100 mL), and washed with brine (30 mL) The EtOAc layer was driedover anhydrous Na₂SO₄ and concentrated under vacuum. The residue waspurified by the silica gel column (20% EtOAc/PE) to give1-(5,8-dimethoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethanone (XV) (800mg, 3.36 mmol, 88% yield) as a white solid. ¹H NMR (CDCl₃, 500 MHz) 6ppm 2.64 (s, 3H), 3.89 (d, J=3.26 Hz, 6H), 4.37 (dd, J=14.56 Hz, 4.77Hz, 41-1), 6.96 (s, 1H).

Step 7

A solution of1-(5,8-dimethoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethanone (XV) (800mg, 3.36 mmol), CuBr₂ (1.13 g, 5.04 mmol) in EtOAc (20 mL), CHCl₃ (20mL) and MeOH (1 mL) was stirred at 50-60° C. for 5 h. This reactionmixture was cooled, diluted with sat aqueous NH₄Cl solution (30 mL), andextracted with EtOAc (50 mL). The organic layer was washed with brine,dried over anhydrous Na₂SO₄, and concentrated under vacuum to give acrude2-bromo-1-(5,8-dimethoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethanone(XVI) (1.1 g, 3.47 mmol). The crude product was used for the next stepwithout any additional purification.

Preparation of intermediate (XXIII) is depicted below in Scheme 5.

Step 1

A solution of 1-(2,3,4-trihydroxyphenyl)ethanone (XVII) (30 g, 0.18mol), 1,2-dibromoethane (33.52 g, 0.18 mol), and K₂CO₃ (74 g, 0.53 mol)in DMF (200 mL) was stirred at 100° C. for 2 h under N₂. The blackreaction mixture was cooled, diluted with water (1000 mL), and extractedwith 40% EtOAc/PE (3×300 mL). The combined organic layers were washedwith brine (3×50 mL), dried over Na₂SO₄ and concentrated under vacuum togive 1-(5-hydroxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethanone (XVIII)(11 g, 56.6 mmol, 33% yield) as a yellow solid. ¹H NMR (CDCl₃, 500 MHz)δ ppm 2.58 (s, 3H), 4.35 (s, 4H), 6.45 (d, J=8.78 Hz, 1H), 7.28 (d,J=9.03 Hz, 1H), 12.86 (s, 1H).

Step 2

A solution of 1-(5-hydroxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl) ethanone(XVIII) (11 g, 56.65 mmol), K₂CO₃ (15.6 g, 0.113 mol) and MeI (16 g,0.113 mol) DMF (80 mL) was stirred at room temperature for 18 h. Thisreaction mixture was diluted with water (300 mL), and extracted with 20%EtOAc/PE (2×200 mL). The combined organic layers were washed with brine(2×100 mL), dried with Na₂SO₄, and concentrated under vacuum to give1-(5-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethanone (XIX) (11 g,52.8 mmol, 94% yield) as a yellow oil. ¹H NMR (CDCl₃, 500 MHz) δ ppm2.60 (s, 3H), 3.93 (s, 3H), 4.32 (s, 4H), 6.67 (d, J=8.78 Hz, 1H), 7.31(d, J=9.03 Hz, 1H).

Step 3

A solution of 1-(5-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethanone(XIX) (11 g, 53 mmol) and m-CPBA (55 g, 0.23 mol), in DCM (120 mL), washeated to 50-60° C. for 18 h. This reaction mixture was cooled andfiltered. The filtrate was diluted with DCM (250 mL) and washed with a50% aqueous NaHSO₃ solution (200 mL), sat NaHCO₃ (200 mL) and brine. TheDCM layer was dried over anhydrous Na₂SO₄ and concentrated under vacuum,purified by column chromatography on silica gel (20% EtOAc/PE) to give5-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl acetate (XX) (6 g, 26.8mmol, 55% yield) as a white solid. ¹H NMR (CDCl₃, 500 MHz) 6 ppm 2.31(s, 3H), 3.85 (s, 3H), 4.19-4.43 (m, 4H), 6.49-6.56 (m, 1H), 6.58-6.65(m, 1H).

Step 4

A solution of 5-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl acetate (XX)(6 g, 26.8 mmol) in HOAc (3 mL), and BF₃*Et₂O (6 mL) was stirred at 100°C. for 2 h. The black reaction solution was cooled down, diluted withEtOAc (150 mL), washed with water (2×50 mL), sat NaHCO₃ solution (50mL), and brine (50 mL) The EtOAc layer was dried over anhydrous Na₂SO₄and concentrated under vacuum. The crude1-(7-hydroxy-8-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethanone(XXI) was used directly for the next step without any additionalpurification.

Step 5

A solution of crude1-(7-hydroxy-8-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethanone(XXI) K₂CO₃ (10 g, 70.9 mmol), and MeI (16 g, 0.19 mmol) in DMF (50 mL)was stirred at 40° C. for 5 h. This reaction mixture was cooled, dilutedwith water (150 mL), and extracted with EtOAc (2×100 mL). The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄,concentrated under vacuum, and purified by column chromatography onsilica gel (20% EtOAc/PE) to produce1-(7,8-dimethoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethanone (XXII) (3g, 12.6 mmol, 47.0% yield for two steps) as a yellow oil. ¹H NMR (CDCl₃,500 MHz) 6 ppm 2.59 (s, 3H), 3.90 (d, J=5.27 Hz, 6H), 4.17-4.27 (m, 2H),4.28-4.41 (m, 2H), 7.09 (s, 1H).

Step 6

A solution of 1-(7,8-dimethoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethanone (XXII) (0.5 g, 2.1 mmol), and CuBr₂ (0.562 g, 2.5 mmol) in amixture of EtOAc (20 mL), CHCl₃ (20 mL), and MeOH (1 mL) was stirred at50-60° C. for 5 h. The reaction mixture was cooled, diluted with EtOAc(60 mL), washed with a sat aqueous NH₄Cl solution (30 mL), brine (30mL), dried over anhydrous Na₂SO₄ and concentrated under vacuum to give acrude2-bromo-1-(7,8-dimethoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethanone(XXIII) as an oil (920 mg) which was used directly for the next stepwithout any further purification.

Preparation of intermediate (VOW) is depicted below in Scheme 6.

Step 1

The mixture of 5-bromo-1,2,3-trimethoxybenzene (XXIV) (50 g, 0.2 mol) inanhydrous DCM (500 mL) was added BBr₃ (167.3 g, 0.66 mol) at −78° C.dropwise while stirring. The black reaction mixture was allowed warm toroom temperature and stir overnight. The reaction mixture was pouredinto ice water (1000 mL), and extracted with EtOAc (2×1000 mL) The EtOAclayers were dried over anhydrous Na₂SO₄, and concentrated to give5-bromobenzene-1,2,3-triol (XXV) as a pale solid. (40 g, 0.195 mol,96.4% yield)¹H NMR (DMSO-d₆, 400 MHz): δ ppm 6.40 (s, 1H), 9.28 (brs,3H); ESIMS found C₆H₅BrO₃ m/z 205.0 (M+H).

Step 2

The mixture of 5-bromobenzene-1,2,3-triol (XXV) (20 g, 97.6 mmol), K₂CO₃(23.8 g, 0.146 mol) and 1,2-dibromoethane (20.16 g, 107.3 mmol) in DMF(200 mL) was stirred at 100° C. for 2 h. The reaction mixture was cooledand diluted with water (600 mL), extracted with 50% EtOAc/PE (3×400 mL).The combined organic layers were washed with brine (3×200 mL), driedover anhydrous Na₂SO₄, and concentrated under vacuo. The residue waspurified by column chromatography on silica gel (20% EtOAc/PE) to give7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-5-ol (XXVI) as a white solid. (4g, 17.3 mmol, 17.7% yield) ¹H NMR (CDCl₃, 400 MHz): δ ppm 4.19-4.38 (m,4H), 5.37 (brs, 1H), 6.62 (d, J=2.01 Hz, 1H), 6.69 (d, J=2.01 Hz, 1H);ESIMS found C₈H₇BrO₃ m/z 230.9 (M+H).

Step 3

To the mixture of 7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-5-ol (XXVI) (6g, 26.0 mmol), and TEA (5.3 g, 52 mmol) in DCM (200 mL), was addedacetyl chloride (3 g, 39 mmol) at 0° C. dropwise which was then stirredat room temperature for 2 h. The reaction mixture was quenched with sat.aq. NaHCO₃ (200 mL), and the water layer was separated. The DCM waswashed with brine (100 mL), dried over anhydrous Na₂SO₄, andconcentrated under vacuum. The residue was purified by columnchromatography on silica gel (20% EtOAc/PE) to give7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-5-yl acetate (XXVII) as a whitesolid. (6.5 g, 23.8 mmol, 91.5% yield)¹H NMR (CDCl₃, 400 MHz): δ ppm2.30 (s, 3H), 4.18-4.34 (m, 4H), 6.80 (d, J=2.26 Hz, 1H), 6.94 (d,J=2.26 Hz, 1H); ESIMS found C₁₀H₉Bra₄ m/z 272.9 (M+H).

Step 4

The mixture of 7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-5-yl acetate(XXVII) (6 g, 22.0 mmol) in HOAc (20 mL), and BF₃*Et₂O (20 mL) wasstirred at 100° C. for 3 h. The reaction solution was cooled, dilutedwith EtOAc (250 mL), washed with water (2×100 mL), sat. aq. NaHCO₃solution (2×150 mL), and brine (100 mL). The EtOAc layer was dried overanhydrous Na₂SO₄ and concentrated. Crude1-(7-bromo-5-hydroxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-one(XXVIII) was used for the next step directly without any purification.ESIMS found C₁₀H₉BrO₄ m/z 273.0 (M+H).

Step 5

A solution of the1-(7-bromo-5-hydroxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-one(XXVIII), K₂CO₃ (6.6 g, 47.6 mmol), and MeI (6.76 g, 47.6 mmol) in DMF(50 mL) was stirred at room temperature overnight. The reaction mixturewas diluted with water (150 mL) and extracted with EtOAc (2×100 mL). Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄, concentrated under vacuum, and purified by column chromatographyon silica gel (20% EtOAc/PE) to give1-(7-bromo-5-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl) ethan-1-one(XXIX) as a yellow oil. (3 g, 10.4 mmol, 47.5% yield for 2 steps)¹H NMR(CDCl₃, 400 MHz): δ ppm 2.50 (s, 311), 3.83 (s, 3H), 4.20-4.37 (m, 4H),6.87 (s, 1H); ESIMS found C₁₁H₁₁BrO₄ m/z 287.0 (M+H).

Step 6

A solution of1-(7-bromo-5-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-one(XXIX) (800 mg, 2.79 mmol) in DMF:H₂O (95:5)(16 mL) was heated at 80° C.for 30 minutes. To this solution was added a solution of 25% NaOMe (1.44g of Na in 16 mL MeOH) in four portions. The temperature of theresulting solution was raised to 110° C. followed by addition of thecatalyst CuBr (112 mg, 0.8 mmol). The reaction mixture was heated underreflux for 6 h. The reaction was cooled and diluted with sat. aq. NH₄Cl(40 mL), extracted with EtOAc (2×). The combined EtOAc layers were driedover anhydrous Na₂SO₄, concentrated, and purified by preparative TLC(10% EtOAc/PE) to give1-(5,7-dimethoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-one (XXX)as a yellow oil. (70 mg, 0.294 mmol, 10.5% yield)¹H NMR (CDCl₃, 400MHz): δ ppm 2.47 (s, 3H), 3.72 (s, 31-1), 3.85 (s, 3H), 4.20-4.33 (m,4H), 6.22 (s, 1H); ESIMS found C₁₂H₁₄O₅ m/z 239.1 (M+H).

Step 7

A mixture of1-(5,7-dimethoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-one (XXX)(130 mg, 0.546 mmol), CuBr₂ (183 mg, 0.82 mmol) in EtOAc (10 mL), CHCl₃(10 mL) and MeOH (0.2 mL) was stirred at 50-60° C. for 5 h. The reactionmixture was cooled, diluted with sat. aq. NH₄Cl (30 mL), and extractedwith EtOAc (50 mL). The combined organic layers were washed with brine,dried over anhydrous Na₂SO₄, and concentrated under vacuum to give acrude2-bromo-1-(5,7-dimethoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-one(XXI) which directly used for the next step without further purification(170 mg). ESIMS found C₁₂H₁₃BrO₅ m/z 317.0 (M+H).

Preparation of1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(dimethylamino)propan-1-one(XXXIII) is depicted below in Scheme 7.

Step 1

A solution of 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethanone (XXXII)(4.68 g, 26.3 mmol), dimethylamine hydrochloride (2.78 g, 34.1 mmol),paraformaldehyde (1.18 g, 39.4 mmol) and 12 N HCl (50 μL) in ethanol(8.0 mL) was refluxed overnight. The solution was cooled to roomtemperature and the ethanol was evaporated under vacuum. The residue wastreated with EtOAc, heated slightly and sonicated to disperse into fineparticles. The solids were filtered and dried at room temperature toproduce 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(dimethylamino)propan-1-one hydrochloride as a white solid, (7.73 g, quantitativeyield). The solid was cooled in minimum about of water (12 mL) andcooled to 0° C. A 20% aqueous solution of NaOH was added until pH=10.The solution was extracted with DCM, dried and evaporated to produce1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(dimethylamino) propan-1-one(XXXIII) a colorless oil (2.485 g, 10.6 mmol, 40.2% yield)¹H NMR (CDCl₃,500 MHz): δ ppm 2.77 (s, 6H), 3.41 (m, 2H), 3.56 (m, 2H), 4.25 (m, 4H),6.85 (m, 1H), 7.45 (m, 2H); ESIMS found C₁₃H₁₇NO₃ m/z 236 (M+H).

The following intermediates were prepared in accordance with theprocedure described in the above Scheme 7.

3-(Dimethylamino)-1-phenylpropan-1-one (XXXIV): Yellow oil, (3.9 g, 22.0mmol, 52.7% yield). ¹H NMR (DMSO-d₆, 400 MHz) δ ppm 2.81 (s, 6H), 3.40(t, J=7.6 Hz, 2H), 3.65 (t, J=7.6 Hz, 2H), 7.58 (t, J=7.6 Hz, 2H), 7.70(t, J=7.6 Hz, 1H), 8.03 (d, J=7.2 Hz, 2H); ESIMS found C₁₁H₁₅NO m/z178.0 (M+H).

3-(Dimethylamino)-1-(2-fluorophenyl)propan-1-one (XXXV): Yellow oil,(11.8 g, 60.4 mmol, 84.0% yield). ESIMS found C₁₁H₁₄FNO m/z 196.2 (M+H).

3-(Dimethylamino)-1-(3-fluorophenyl)propan-1-one (XXXVI): Yellow oil,(10.3 g, 52.8 mmol, 72.8% yield). ¹H NMR (CDCl₃, 400 MHz) δ ppm 2.31 (s,6H), 2.78 (t, J=7.2 Hz, 2H), 3.15 (t, J=7.2 Hz, 2H), 7.29 (t, 1H), 7.47(dq, J=8.0 Hz, J=2.4 Hz, 1H), 7.66 (d, J=9.6 Hz, 1H), 7.76 (d, J=8.0 Hz,1H); ESIMS found C₁₁H₁₄FNO m/z 196.1 (M+H).

3-(Dimethylamino)-1-(4-fluorophenyl)propan-1-one (XXXVII): Yellow oil,(12.0 g, 61.5 mmol, 85.0% yield). ESIMS found C₁₁H₁₄FNO m/z 196.1 (M+H).

3-(Dimethylamino)-1-(2-(trifluoromethyl)phenyl)propan-1-one (XXXVIII):Yellow oil, (1.6 g, 6.5 mmol, 24.6% yield). ¹H NMR (CDCl₃, 400 MHz) 6ppm 2.27 (s, 61-1), 2.72 (t, J=7.2 Hz, 2H), 3.04 (t, J=7.2 Hz, 2H), 7.47(d, J=7.2 Hz, 1H), 7.52-7.67 (m, 2H), 7.72 (d, J=7.2 Hz, 1H); ESIMSfound C₁₂H₁₄F₃NO m/z 246.0 (M+H).

3-(Dimethylamino)-1-(3-(trifluoromethyl)phenyl)propan-1-one (XXXIX):Yellow oil, (7.9 g, 32.2 mmol, 64.0% yield). ESIMS found C₁₂H₁₄F₃NO m/z246.1 (M+H).

3-(Dimethylamino)-1-(4-(trifluoromethyl)phenyl)propan-1-one (XL): Yellowoil, (9.5 g, 38.7 mmol, 77.0% yield). ESIMS found C₁₂H₁₄F₃NO m/z 246.1(M+H).

3-(Dimethylamino)-1-(o-tolyl)propan-1-one (XLI): Yellow oil, (5.1 g,26.7 mmol, 71.8% yield). ¹H NMR (CDCl₃, 400 MHz) δ ppm 2.28 (s, 6H),2.50 (s, 3H), 2.73 (t, J=7.6 Hz, 2H), 3.09 (t, J=7.6 Hz, 2H), 7.27 (t,J=8.4 Hz, 2H), 7.38 (t, J=7.6 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H); ESIMSfound C₁₂H₁₇NO m/z 192.1 (M+H).

3-(Dimethylamino)-1-(m-tolyl)propan-1-one (XLII): Yellow oil, (5.2 g,27.2 mmol, 73.2% yield). ¹H NMR (CDCl₃, 400 MHz) δ ppm 2.30 (s, 6H),2.42 (s, 3H), 2.67 (t, J=7.6 Hz, 2H), 3.15 (t, J=7.6 Hz, 2H), 7.31-7.43(m, 2H), 7.71-7.82 (m, 2H); ESIMS found C₁₂H₁₇NO m/z 192.1 (M+H).

3-(Dimethylamino)-1-(p-tolyl)propan-1-one (XLIII): Yellow oil, (5.1 g,25.6 mmol, 71.8% yield). ¹H NMR (CDCl₃, 400 MHz) δ ppm 2.31 (s, 6H),2.43 (s, 3H), 2.77 (t, J=7.6 Hz, 2H), 3.15 (t, J=7.6 Hz, 2H), 7.28 (d,J=8.0 Hz, 2H), 7.88 (d, J=8.0 Hz, 2H); ESIMS found C₁₂H₁₇NO m/z 192.0(M+H).

3-(Dimethylamino)-1-(2-methoxyphenyl)propan-1-one (XLIV): Yellow oil,(3.1 g, 15.0 mmol, 45.6% yield). ¹H NMR (CDCl₃, 400 MHz) δ ppm 2.25 (s,6H), 2.69 (t, J=7.2 Hz, 2H), 3.17 (t, J=7.2 Hz, 2H), 3.88 (s, 3H),6.88-7.03 (m, 2H), 7.43 (t, J=7.8 Hz, 1H), 7.67 (d, J=8 Hz, 1H); ESIMSfound C₁₂H₁₇NO₂ m/z 208.1 (M+H).

3-(Dimethylamino)-1-(3-methoxyphenyl)propan-1-one (XLV): Yellow oil,(5.0 g, 24.1 mmol, 72.4% yield). ¹H NMR (CDCl₃, 400 MHz) δ ppm 2.32 (s,6H), 2.79 (t, J=7.6 Hz, 2H), 3.17 (t, J=7.6 Hz, 2H), 3.86 (s, 3H), 7.12(dd, J=8.4 Hz, J=2.8 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.51 (d, J=2.5 Hz,1H), 7.56 (d, J=8.0 Hz, 1H); ESIMS found C₁₂H₁₇NO₂ m/z 208.1 (M+H).

3-(Dimethylamino)-1-(4-methoxyphenyl)propan-1-one (XLVI): Yellow oil,(5.0 g, 24.1 mmol, 72.4% yield). ¹H NMR (CDCl₃, 400 MHz) δ ppm 2.29 (s,6H), 2.74 (t, J=7.6 Hz, 2H), 3.10 (t, J=7.6 Hz, 2H), 3.86 (s, 3H), 6.93(d, J=8.6 Hz, 2H), 7.95 (d, J=8.6 Hz, 2H); ESIMS found C₁₂H₁₇NO₂ m/z208.1 (M+H).

3-(Dimethylamino)-1-(thiophen-2-yl)propan-1-one (XLVII): Yellow oil,(5.1 g, 27.8 mmol, 69.9% yield). ¹H NMR (CDCl₃, 400 MHz) δ ppm 2.30 (s,6H), 2.77 (t, J=7.4 Hz, 2H), 3.10 (t, J=7.4 Hz, 2H), 7.14 (t, J=7.6 Hz,1H), 7.64 (dd, J=5.2 Hz, J=0.4 Hz, 1H), 7.74 (dd, J=4.0 Hz, J=0.8 Hz,1H); ESIMS found C₉H₁₃NOS m/z 184 (M+H).

3-(Dimethylamino)-1-(furan-2-yl)propan-1-one (XLVIII): Yellow oil, (4.3g, 25.7 mmol, 56.6% yield). ¹H NMR (CDCl₃, 400 MHz) δ ppm 2.27 (s, 6H),2.73 (t, J=7.4 Hz, 21-1), 3.00 (t, J=7.4 Hz, 2H), 6.53 (td, J=3.6 Hz,J=1.6 Hz, 1H), 7.19 (d, J=3.6 Hz, 111), 7.58 (d, J=5.2 Hz, 1H); ESIMSfound C₉H₁₃NO₂ m/z 168 (M+H).

3-(Dimethylamino)-1-(5,6,7,8-tetrahydronaphthalen-2-yl)propan-1-one(XLIX): White solid (7.3 g, 31.5 mmol, 93% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 1.75-1.77 (m, 411), 2.79 (s, 6H), 2.78-2.81 (m, 4H),3.36-3.39 (m, 21-1), 3.54-3.57 (m, 2H), 7.23 (d, J=7.9 Hz, 1H),7.70-7.72 (m, 2H), 10.53 (brs, 1H); ESIMS found C₁₅H₂₁NO m/z 232.0(M+H).

1-(Benzo[d][1,3]dioxol-5-yl)-3-(dimethylamino)propan-1-one (L): Whitesolid (16.9 g, 76.4 mmol, 100% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm2.79 (s, 6H), 3.35-3.38 (m, 2H), 3.51-3.54 (m, 2H), 6.16 (s, 2H), 7.09(d, J=8.2 Hz, 1H), 7.49 (d, J=1.7 Hz, 1H), 7.67 (dd, J=1.7 Hz, J=8.2 Hz,1H), 10.51 (brs, 1H); ESIMS found C₁₂H₁₅NO₃ m/z 221.9 (M+H).

1-(Chroman-6-yl)-3-(dimethylamino)propan-1-one (LI): White solid (3.99g, 17.1 mmol, 99.5% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 1.95 (quin,J=5.80 Hz, 2H), 2.77-2.85 (m, 914), 3.37 (t, J=7.14 Hz, 2H), 3.51 (t,J=7.14 Hz, 2H), 4.23 (t, J=5.00 Hz, 2H), 6.86 (d, J=8.78 Hz, 1H), 7.74(dd, J=8.51, 2.47 Hz, 1H), 7.78 (d, J=2.20 Hz, 1H), 10.44 (brs, 1H);ESIMS found C₁₄H₁₉NO₂ m/z 234.1 (M+H).

Preparation of chromane-6-carbaldehyde (LIV) is depicted below in Scheme8.

Step 1

To a solution of dimethylamine hydrochloride (2.25 g, 27.6 mmol) in EtOH(212 mL) was added TEA (3.84 mL, 27.6 mmol). 2-Bromobenzaldehyde (LII)(5.1 g, 27.6 mmol) was then added and the reaction was stirredovernight. NaCNBH₃ (3.47 g, 55.1 mmol) was then added and the reactionstirred at room temperature for 6 h. The solvent was removed under nighvacuum. The residue was dissolved in DCM, washed with sat. aq. NaHCO₃,washed with water and then with brine, dried over MgSO₄ andconcentrated. The crude product was purified on a silica gel column(100% EtOAc→15% hexane/EtOAc) to give1-(2-bromophenyl)-N,N-dimethylmethanamine (LIII) as a colorless liquid(3.46 g, 16.2 mmol, 58.6% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 2.19(s, 6H), 3.45 (s, 2H), 7.18-7.22 (m, 1H), 7.35-7.38 (m, 1H), 7.45 (dd,J=1.7 Hz, J=7.6 Hz, 1H), 7.59 (dd, J=1.1 Hz, J=8.0 Hz, 1H); ESIMS foundC₉H₁₂BrN m/z 213.8 (M+H).

Step 2

To a solution of 1-(2-bromophenyl)-N,N-dimethylmethanamine (LIII) in THF(25 mL) cooled to −78° C. under N₂ was added a 2.5M solution of nBuLi inhexane (3.37 mL, 8.42 mmol). The reaction was stirred at −78° C. underN₂ for 1.5 h before adding DMF (0.68 mL, 8.79 mmol). The reaction wasstirred at −78° C. under N₂ for 1 h and then warmed to room temperature.The solvent was removed under reduced pressure and purified on a silicacolumn (100% CHCl₃→10% MeOH/CHCl₃) to produce2-((dimethylamino)methyl)benzaldehyde (LIV) as a light yellow oil (305mg, 1.87 mmol, 25.5% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 2.14 (s,6H), 3.72 (s, 2H), 7.42 (d, J=7.6 Hz, 1H), 7.45-7.48 (m, 1H), 7.57-7.59(m, 1H), 7.78 (dd, J=1.2 Hz, J=7.6 Hz, 1H), 10.34 (s, 1H); ESIMS foundC₉H₁₂BrN m/z 163.9 (M+H).

Preparation of chromane-6-carbaldehyde (LVII) is depicted below inScheme 9.

Step 1

To a suspension of zinc dust (100 g, 1.56 mol) in HOAc (300 mL) wasadded chroman-4-one (LV) (10 g, 67.6 mol). The mixture was stifled at110° C. for 6 h. Then the mixture was cooled and filtrated. The filtratewas poured into water (500 mL) and extracted with EtOAc (3×100 mL). Theorganic layer was concentrated to give chromane (LVI) as colorless oil.(8.05 g, 60.0 mmol, 88.7% yield). ¹H NMR (CDCl₃, 400 MHz) δ ppm 2.04 (q,J=4.3 Hz, 2H), 2.81 (t, J=6.6 Hz, 2H), 4.21 (t, J=5.2 Hz, 2H), 6.72-6.92(m, 2H), 7.00-7.17 (m, 2H); ESIMS found C₉H₁₀O m/z 135.0 (M+H).

Step 2

To a solution of chromane (LVI) (3 g, 22.4 mmol, 1.0 eq) and DMF (3.3 g,45.2 mmol, 2 eq) in DCE (20 mL) was added phosphorus oxychloride (3.4 g,45.2 mmol, 2 eq) dropwise over 30 min below 50° C. The mixture wasstirred at 85° C. for 12 h. The reaction was quenched by water andextracted with EtOAc (3×300 mL). The combined organic phase was driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by chromatography on silica gel (PE:EtOAc=8:1) to givechromane-6-carbaldehyde (LVII) as yellow oil. (2.0 g, 12.3 mmol, 55.1%yield). ¹H NMR (CDCl₃, 400 MHz) δ ppm 2.01 (q, J=45.8 Hz, 2H), 2.82 (t,J=6.4 Hz, 2H), 4.24 (t, J=5.2 Hz, 2H), 6.85 (d, J=8.4 Hz, 1H), 7.52-7.64(m, 2H), 9.79 (s, 1H); ESIMS found C₁₀H₁₀O₂ m/z 163.1 (M+H).

Preparation of benzo[d]oxazole-5-carbaldehyde (LXI) is depicted below inScheme 10.

Step 1

A solution of 2-amino-4-bromophenol (LVIII) (10 g, 53.5 mmol, 1 eq) intrimethyl orthoformate (200 mL) was stirred at reflux for 2 h. Aftercooling, the solution was concentrated under reduced pressure to removetrimethyl orthoformate to give 5-bromobenzo[d]oxazole (LIX) (10.06 g,50.8 mmol, 95.0%). Used in the next reaction without additionalpurification.

Step 2

To a suspension of 5-bromobenzo[d]oxazole (LIX) (10.06 g, 50.8 mmol, 1eq) in dioxane (200 mL) and water (10 mL) was added potassium(ethenyl)trifluoroborate (8.17 g, 61 mmol, 1.2 eq), cesium carbonate(13.8 g, 101.6 mmol, 2 eq) and tetrakis(triphenylphosphorus)palladium(0) (2.9 g, 2.54 mmol, 0.05 eq). The mixture was stirred atreflux under nitrogen for 5 h. The mixture was then poured ontoice-water (200 mL) and extracted with EtOAc (3×300 mL). The organicphases were combined, dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo, the residue was purified by chromatography onsilica gel (PE:EtOAc=20:1>10:1) to afford 5-vinylbenzo[d]oxazole (LX)(6.11 g, 42.1 mmol, 82.9%) as an oil. Used in the next reaction directlywithout additional purification.

Step 3

To a solution of 5-vinylbenzo[d]oxazole (LX) (6.1 g, 42.1 mmol, 1.0 eq)in DCM (100 mL) was bubbled ozone at −78° C. until the solution turn toblue. The solution was then purged with O₂ followed by N₂ for 5 minutes.TEA (12.8 g, 126.3 mmol, 3 eq) was added and the mixture was stirred at25° C. for 1 h. The solution was poured into water (200 mL) andextracted with EtOAc (3×300 mL). The combined organic phase was dried,filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel eluted (PE:EtOAc=10:1→1:1) to givebenzo[d]oxazole-5-carbaldehyde (LXI) (2.1 g, 14.3 mmol, 33.9%) as acolorless oil. ¹H NMR (CDCl₃, 400 MHz) δ ppm 7.75 (d, J=8.4 Hz, 1H),8.02 (dd, J=8.4 Hz, J=1.2 Hz, 1H), 8.22 (s, 1H), 8.33 (s, 1H), 10.13 (s,1H); ESIMS found C₈H₅NO₂ m/z 148.0 (M+H).

Preparation of 2,3-dihydrobenzo[b][1,4]oxathiine-6-carbaldehyde (LXIV)is depicted below in Scheme 11.

Step 1

To a solution of 2-mercaptophenol (LXII) (10 g, 79 mmol, 1.0 eq) inacetone (500 mL) was added potassium carbonate (21.8 g, 158 mmol, 2 eq)and 1,2-dibromoethane (14.92 g, 79 mmol, 1 eq) in acetone (100 mL)dropwise over 3 h. The mixture was stirred at 30° C. for 12 h. The solidwas filtered off and the filtrate was concentrated in vacuo. The residuewas purified by chromatography on silica gel (100% PE) to give2,3-dihydrobenzo[b][1,4]oxathiine (LXIII) as colorless oil. (4.02 g,26.4 mmol, 33.3%) as a colorless oil. ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.14(t, J=4.6 Hz, 2H), 4.43 (t, J=4.6 Hz, 2H), 6.71-6.92 (m, 2H), 7.02 (td,J=7.6 Hz, J=1.6 Hz, 1H), 7.07 (dd, J=7.6 Hz, J=1.2 Hz, 1H); ESIMS foundC₈H₈OS m/z 153.0 (M+H).

Step 2

To a solution of 2,3-dihydrobenzo[b][1,4]oxathiine (LXIII) (4 g, 26.3mmol, 1.0 eq) and DMF (7.2 g, 47.2 mmol, 2 eq) in DCE (20 mL) was addedphosphorus oxychloride (3.4 g, 47.2 mmol, 2 eq) dropwise over 30 minutesbelow 50° C. The mixture was stirred at 85° C. for 12 h. The reactionwas quenched by water and extracted with EtOAc (3×300 mL). The combinedorganic phase was dried, filtered and concentrated in vacuo, the residuewas purified by chromatography on silica gel (PE:EtOAc=10:1→5:1) to give2,3-dihydrobenzo[b][1,4]oxathiine-6-carbaldehyde (LXIV) as yellow oil.(300 mg, 1.67 mmol, 6.3%) as a colorless oil. ¹H NMR (CDCl₃, 400 MHz) δppm 3.15 (t, J=4.6 Hz, 2H), 4.50 (t, J=4.6 Hz, 2H), 6.92 (d, J=8.4 Hz,1H), 7.51 (dd, J=8.8 Hz, J=2.0 Hz, 1H), 7.59 (s, 1H), 9.80 (s, 1H);ESIMS found C₉H₈O₂S m/z 181.1 (M+H).

Preparation of 2,3-dihydrobenzo[b][1,4]dioxin-5-carbaldehyde (LXVI) isdepicted below in Scheme 12.

Step 1

To a solution of 2,3-dihydroxybenzaldehyde (LXV) (5 g, 36.2 mmol, 1.0eq) in acetone (300 mL) was added potassium carbonate (10 g, 72.5 mmol,2 eq) and 1,2-dibromoethane (6.8 g, 36.2 mmol, 1 eq) in acetone (50 mL)dropwise over 2 h. The mixture was stirred at 30° C. for 12 h. The solidwas filtered off, the filtrate was concentrated in vacuo and purified bychromatography on silica gel (PE:EtOAc=10:1) to give2,3-dihydrobenzo[b][1,4]dioxine-5-carbaldehyde (LXVI) as a colorlessoil. (4.02 g, 26.4 mmol, 68%) ESIMS found C₉H₈O₃ z 165.0 (M+H).

Preparation of benzo[b]thiophene-5-carbaldehyde (LXXI) is depicted belowin Scheme 13.

Step 1

A solution of 5-bromobenzo[b]thiophene (LXVII) (1.2 g, 6 mmol), zinccyanide (0.66 g, 6 mmol) and tetrakis(triphenylphosphorus)palladium (0)(0.65 g, 0.6 mmol) in dry DMF (10 mL) was stirred at reflux undernitrogen atmosphere for 1 h. The mixture was poured into cold water andextracted with EtOAc (3×). The combined organic layers were concentratedin vacuum to give the crude benzo[b]thiophene-5-carbonitrile (LXVIII) asa white solid. (0.90 g, 6 mmol, 100%) ESIMS found C₉H₅NS m/z 160.0(M+H).

Step 2

A suspension of benzo[b]thiophene-5-carbonitrile (LXVIII) (0.9 g, 5.1mmol) and LiOH (10 g, 0.24 mol) in water (50 ml) was stirred at refluxfor 2 h. The reaction was washed with water, acidified to pH 3 with 1MHCl and extracted with EtOAc. The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated in vacuum to give thecrude benzo[b]thiophene-5-carboxylic acid (LXIX) as a white solid. (0.9g, 5.1 mmol, 88.6%) ESIMS found C₉H₆O₂S m/z 179.1 (M+H).

Step 3

To a solution of benzo[b]thiophene-5-carboxylic acid (LXIX) (0.9 g, 5.1mmol) in THF (20 mL) was added LAH (0.28 g, 7 mmol) in portions at 0° C.under nitrogen atmosphere. The reaction was quenched by water, washedwith 20% aq. NaOH (4 mL) and extracted with EtOAc. The EtOAc phase wasconcentrated in vacuo to give the crude benzo[b]thiophen-5-ylmethanol(LXX) as yellow solid. (˜1 g, used without further purification) ESIMSfound C₉H₈OS m/z 165.0 (M+H).

Step 4

To a solution of benzo[b]thiophen-5-ylmethanol (LXX) (˜1 g, crude) inDCM (20 mL) was added manganese oxide (6.36 g, 0.07 mol). The mixturewas stirred at room temperature overnight. The mixture was filtered andthe filtrate was concentrated in vacuo. The residue was purified bychromatography on silica gel (PE: EtOAc=10:1) to givebenzo[b]thiophene-5-carbaldehyde (LXXI) as an orange solid. (570 mg,3.51 mmol, 68.9% yield for 2 steps)¹H NMR (DMSO-d₆, 400 MHz) δ ppm 7.68(d, J=5.2 Hz, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.95 (d, J=5.2 Hz, 1H), 8.23(d, J=8.4 Hz, 1H), 8.48 (s, 1H), 10.11 (s, 1H); ESIMS found C₉H₆OS m/z163.0 (M+H).

Preparation of tert-butyl 5-formyl-1H-benzo[d]imidazole-1-carboxylate(LXXIII) and tert-butyl 6-formyl-1H-benzo[d]imidazole-1-carboxylate(LXXIV) is depicted below in Scheme 14.

Step 1

A solution of 1H-benzo[d]imidazole-5-carbaldehyde (LXXII) (787 mg, 4.92mmol, 1 eq) in DCM (5 mL) was added Boc₂O (1.13 g, 5.2 mmol, 1.05 eq)and DMAP (60 mg, 0.492 mmol, 0.1 eq). The mixture was then stirred at25° C. for 30 minutes before being poured into water (100 mL) andextracted with EtOAc (3×100 mL), the organic phases were combined, driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo to give amixture of tert-butyl 5-formyl-1H-benzo[d]imidazole-1-carboxylate(LXXIII) and tert-butyl 6-formyl-1H-benzo[d]imidazole-1-carboxylate(LXXIV) as a white solid. (850 mg, 63.5%)¹H NMR (CDCl₃, 400 MHz) δ ppm1.73 (s, 9H), 7.93 (s, 1H), 7.98 (dd, J=8.4 Hz, J=1.2 Hz, 1H), 8.16 (d,J=8.4 Hz, 1H), 8.30 (s, 1H), 8.55 (s, 1H), 8.60 (s, 1H), 10.12 (s, 1H);ESIMS found C₁₃H₁₄N₂O₃ m/z 247.1 (M+H).

The following intermediates were prepared in accordance with theprocedure described in the above Scheme 14.

tert-Butyl 5-formyl-1H-indole-1-carboxylate (LXXV): White solid, (8.5 g,34.7 mmol, 50.3% yield). ¹H NMR (CDCl₃, 400 MHz) δ ppm 1.70 (s, 9H),6.70 (d, J=4.0 Hz, 1H), 7.70 (d, J=4.0 Hz, 1H), 7.87 (dd, J=8.8 Hz,J=1.6 Hz, 1H), 8.11 (s, 1H), 8.30 (d, J=8.8 Hz, 1H), 10.08 (s, 1H);ESIMS found C₁₄H₁₅NO₃ m/z 246.1 (M+H).

tert-Butyl 5-formyl-1H-indazole-1-carboxylate (LXXVI): White solid, (1.8g, 7.3 mmol, 93.3% yield). ¹H NMR (CDCl₃, 400 MHz) δ ppm 1.76 (s, 9H),8.10 (d, J=8.8 Hz, 1H), 8.30 (s, 1H), 8.34 (s, 1H), 8.35 (d, J=8.8 Hz,1H), 10.13 (s, 1H); ESIMS found C₁₃H₁₄N₂O₃ m/z 247.1 (M+H).

tert-Butyl 3-formyl-1H-indazole-1-carboxylate (LXXVIIa) and tert-butyl3-formyl-2H-indazole-2-carboxylate (LXXVIIb): White solid, (1.6 g, 6.5mmol, 38.1% yield). ¹H NMR (CDCl₃, 400 MHz) δ ppm 1.77 (s, 9H), 7.45 (t,J=7.4 Hz, 1H), 7.60 (t, J=7.4 Hz, 1H), 8.18 (d, J=8.4 Hz, 1H), 8.32 (d,J=8.4 Hz, 1H), 10.34 (s, 1H); ESIMS found C₁₃H₁₄N₂O₃ m/z 247.1 (M+H).

Example 1

Preparation of1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-(3-(trifluoromethyl)phenyl)butane-1,4-dione(1) is depicted below in Scheme 15.

Step 1

To a solution of1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(dimethylamino)propan-1-one(XXXIII) (1.05 g, 4.4 mmol) and 2-(trifluoromethyl)benzaldehyde(LXXVIII) (703 μL, 5.3 mmol) in TEA (2.0 mL, 14.2 mmol) and was added3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (336 mg, 1.3mmol). The solution was heated overnight at 85° C. The solution wascooled and excess solvent was evaporated under vacuum. The residue waspartitioned between EtOAc and water. The organic phase was dried overMgSO₄, filtered and concentrated. The residue was purified by silica gelflash chromatography using (100% hexane→EtOAc/hexane=1:9) to yield1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-(3-(trifluoromethyl)phenyl)butane-1,4-dione1 as an opaque oil (127.3 mg, 0.35 mmol, 7.8% yield). ¹H NMR (DMSO-d₆,500 MHz) 6 ppm 3.22-3.25 (m, 2H), 3.33-3.35 (m, 2H), 4.29-4.30 (m, 2H),4.33-4.35 (m, 2H), 6.99 (d, J=8.4 Hz, 1H), 7.50 (d, J=2.2 Hz, 1H), 7.55(dd, J=8.4 Hz, J=2.0 Hz, 1H), 7.72-7.75 (m, 1H), 7.82-7.86 (m, 2H), 7.94(d, J=7.5 Hz, 1H); ESIMS found C₁₉H₁₅F₃O₄ m/z 365 (M+H).

The following compounds were prepared in accordance with the proceduredescribed in the above Example 1.

1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-(3-fluorophenyl)butane-1,4-dione2

White solid (308.2 mg, 0.98 mmol, 10.4% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 3.29-3.33 (m, 2H), 4.29-4.30 (m, 2H), 4.33-4.34 (m, 2H), 6.99(d, J=8.5 Hz, 1H), 7.34-7.39 (m, 2H), 7.47 (d, J=2.1 Hz, 1H), 7.54 (dd,J=8.5 Hz, J=2.1 Hz, 1H), 7.67-7.69 (m, 1H), 7.82-7.86 (m, 1H); ESIMSfound C₁₈H₁₅FO₄ m/z 315.0 (M+H).

1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-4-(3-(trifluoromethyl)phenyl)butane-1,4-dione9

White solid (30 mg, 0.08 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.39-3.48(m, 4H), 4.30 (d, J=5.2 Hz, 2H), 4.34 (d, J=5.2 Hz, 2H), 6.94(AA′BB′quartet, 1H), 7.77-7.61 (m, 2H), 7.64 (t, J=8 Hz, 1H), 7.84 (d,J=8 Hz, 1H), 8.23 (d, J=8 Hz, 1H), 8.29 (s, 1H); ESIMS found C₁₉H₁₅F₃O₄m/z 365.0 (M+H).

1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-4-(4-(trifluoromethyl)phenyl)butane-1,4-dione10

White solid (25 mg, 0.07 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.45 (s,4H), 4.32 (d, J=5.2 Hz, 2H), 4.35 (d, J=5.2 Hz, 2H), 6.96(AA′BB′quartet, 1H), 7.56-7.64 (m, 2H), 7.77 (d, J=8.4 Hz, 2H), 8.16 (d,J=8 Hz, 2H); ESIMS found C₁₉H₁₅F₃O₄ m/z 365.1 (M+H).

1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-4-(3-fluorophenyl)butane-1,4-dione11

White solid (35 mg, 0.11 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.42 (s,4H), 4.31 (t, J=5.6 Hz, 2H), 4.35 (t, J=5.6 Hz, 2H), 6.95(AA′BB′quartet, 1H), 7.27-7.32 (m, 1H), 7.48 (q, J=5.6 Hz, 1H), 7.60(dd, J=4 Hz, J=2.4 Hz, 2H), 7.73 (d, J=9.2 Hz, 1H), 7.85 (d, J=8 Hz,1H); ESIMS found C₁₈H₁₅FO₄ m/z 314.9 (M+H).

1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-4-(2-methoxyphenyl)butane-1,4-dione12

White solid (20 mg, 0.06 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.33 (t,J=6.4 Hz, 2H), 3.43 (t, J=6.4 Hz, 2H), 3.93 (s, 3H), 4.24-4.38 (m, 4H),6.92 (AA′BB′quartet, 1H), 6.95-7.07 (m, 2H), 7.47 (dt, 1H), 7.53-7.62(m, 2H), 7.76 (dd, J=1.6 Hz, J=7.6 Hz, 1H); ESIMS found C₁₉H₁₈O₅ m/z327.0 (M+H).

1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-4-(3-methoxyphenyl)butane-1,4-dione13

White solid (13 mg, 0.04 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.37-3.43(m, 2H), 3.43-3.48 (m, 2H), 3.88 (s, 3H), 4.29-4.33 (m, 2H), 4.33-4.37(m, 2H), 6.95 (AA′BB′quartet, 1H), 7.12 (dd, J=4 Hz, J=8.8 Hz, 1H), 7.41(t, J=7.6 Hz, 2H), 7.56 (t, J=2.4 Hz, 1H), 7.57-7.62 (m, 2H), 7.66 (d,J=8.4 Hz, 1H); ESIMS found C₁₉H₁₈O₅ m/z 327.1 (M+H).

1-(2,3-Dihydrobenzo[b][1,4]oxathiin-6-yl)-4-(2-(trifluoromethyl)phenyl)butane-1,4-dione16

Yellow oil (16 mg, 0.04 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.13-3.19(m, 2H), 3.22-3.30 (m, 2H), 3.36-3.45 (m, 2H), 4.47-4.55 (m, 2H), 6.89(d, J=8.58 Hz, 1H), 7.57 (t, J=7.76 Hz, 1H), 7.62-7.80 (m, 5H); ESIMSfound C₁₉H₁₅F₃O₃S m/z 380.9 (M+H).

1-(2,3-Dihydrobenzo[b][1,4]oxathiin-6-yl)-4-(4-(trifluoromethyl)phenyl)butane-1,4-dione18

White solid (52 mg, 0.14 mmol). ¹H NMR (DMSO-d₆, 400 MHz) 8 ppm 3.24(dd, J=5.27 Hz, J=4.02 Hz, 2H), 3.36-3.39 (m, 2H), 3.39-3.45 (m, 2H),4.39-4.49 (m, 2H), 6.95 (d, J=8.53 Hz, 1H), 7.67 (dd, J=8.66 Hz, J=2.13Hz, 1H), 7.77 (d, J=2.01 Hz, 1H), 7.93 (d, J=8.28 Hz, 2H), 8.21 (d,J=8.28 Hz, 2H); ESIMS found C₁₉H₁₅F₃O₃S m/z 380.9 (M+H).

1-(2,3-Dihydrobenzo[b][1,4]oxathiin-6-yl)-4-(2-fluorophenyl)butane-1,4-dione19

Yellow oil (11 mg, 0.03 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.14-3.18(m, 2H), 3.34-3.40 (m, 2H), 3.41-3.45 (m, 2H), 4.47-4.52 (m, 2H), 6.88(d, J=8.53 Hz, 1H), 7.12-7.20 (m, 1H), 7.24 (td, J=7.76, 1.00 Hz, 1H),7.47-7.58 (m, 2H), 7.69 (dd, J=8.53, 2.26 Hz, 1H), 7.78 (d, J=2.01 Hz,1H), 7.91 (td, J=7.65, 2.01 Hz, 1H); ESIMS found C₁₈H₁₅FO₃S m/z 330.9(M+H).

1-(2,3-Dihydrobenzo[b][1,4]oxathiin-6-yl)-4-(4-fluorophenyl)butane-1,4-dione21

White solid (15 mg, 0.05 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.15-3.20(m, 2H), 3.38-3.43 (m, 4H), 4.49-4.58 (m, 2H), 6.90 (d, J=8.53 Hz, 1H),7.12-7.21 (m, 2H), 7.70 (dd, J=8.53 Hz, J=2.26 Hz, 1H), 7.80 (d, J=2.01Hz, 1H), 8.05-8.11 (m, 2H); ESIMS found C₁₇H₁₅NO₄ m/z 330.9 (M+H).

1-(2,3-Dihydrobenzo[b][1,4]oxathiin-6-yl)-4-phenylbutane-1,4-dione 28

White solid (8 mg, 0.03 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.14-3.20(m, 2H), 3.36-3.43 (m, 2H), 3.43-3.49 (m, 2H), 4.48-4.56 (m, 2H), 6.90(d, J=8.53 Hz, 1H), 7.46-7.53 (m, 2H), 7.57-7.63 (m, 1H), 7.71 (dd,J=8.53 Hz, J=2.26 Hz, 1H), 7.81 (d, J=2.26 Hz, 1H), 8.02-8.10 (m, 2H);ESIMS found C₁₈H₁₆O₃S m/z 312.9 (M+H).

1-(Chroman-7-yl)-4-(2-methoxyphenyl)butane-1,4-dione 61

Yellow oil (30 mg, 0.09 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 2.84 (t,J=6.40 Hz, 2H), 3.31-3.38 (m, 2H), 3.40-3.48 (m, 2H), 3.93 (s, 3H),4.21-4.29 (m, 2H), 6.83 (d, J=8.28 Hz, 1H), 6.95-7.08 (m, 2H), 7.4207.52(m, 1H), 7.74-7.83 (m, 3H); ESIMS found C₂₀H₂₀O₄ m/z 325.0 (M+H).

1-(Chroman-6-yl)-4-(2-(trifluoromethyl)phenyl)butane-1,4-dione 68

Yellow oil (35 mg, 0.10 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 1.99-2.08(m, 2H), 2.84 (t, J=6.40 Hz, 2H), 3.27 (t, J=6.04 Hz, 2H), 3.43 (t,J=7.32 Hz, 211), 4.26 (t, J=5.28 Hz, 2H), 6.84 (d, J=8.15 Hz, 1H), 7.57(t, J=7.52 Hz 1H), 7.66 (t, J=7.52 Hz, 1H), 7.69-7.83 (m, 4H); ESIMSfound C₂₀H₁₇F₃O₃ m/z 363.0 (M+H).

1-(Chroman-6-yl)-4-(3-(trifluoromethyl)phenyl)butane-1,4-dione 69

White solid (52 mg, 0.14 mmol). ¹H NMR (DMSO-d₆, 400 MHz) 6 ppm1.90-2.03 (m, 2H), 2.82 (t, J=6.40 Hz, 2H), 3.37 (d, J=2.76 Hz, 2H),3.41-3.48 (m, 1H), 4.19-4.29 (m, 2H), 6.85 (d, J=8.53 Hz, 1H), 7.75 (dd,J=8.53 Hz, J=2.26 Hz, 1H), 7.78-7.85 (m, 2H), 8.05 (d, J=7.78 Hz, 1H),8.26 (s, 1H), 8.34 (d, J=7.78 Hz, 1H); ESIMS found C₂₀H₁₇F₃O₃ m/z 363.1(M+H).

1-(Chroman-6-yl)-4-(2-fluorophenyl)butane-1,4-dione 71

White solid (20 mg, 0.06 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 1.98-2.11(m, 2H), 2.85 (t, J=6.8 Hz, 2H), 3.34-3.48 (m, 4H), 4.26 (t, J=5.6 Hz,2H), 6.84 (d, J=8.4 Hz, 1H), 7.16 (ABX quartet, 1H), 7.24 (t, J=7.6 Hz,1H), 7.47-7.58 (m, 1H), 7.78 (s, 1H), 7.81 (d, J=2 Hz, 1H), 7.91 (dt,J=1.6 Hz, J=7.6 Hz, 1H); ESIMS found C₁₉H₁₇FO₃ m/z 313.0 (M+H).

1-(Chroman-6-yl)-4-(4-methoxyphenyl)butane-1,4-dione 76

White solid (20 mg, 0.06 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 2.04(quin, J=6 Hz, 2H), 2.84 (t, J=6.4 Hz, 2H), 3.33-3.46 (m, 4H), 3.89 (s,3H), 4.26 (t, J=5.6 Hz, 2H), 6.84 (d, J=8.8 Hz, 1H), 6.96 (d, J=8.8 Hz,2H), 7.80 (A₂X doublet, 2H), 8.03 (d, J=8.8 Hz, 2H); ESIMS foundC₂₀H₂₀O₄ m/z 325.0 (M+H).

1-(Chroman-6-yl)-4-phenylbutane-1,4-dione 80

White solid (16 mg, 0.05 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 2.05 (q,J=6.4 Hz, 2H), 2.85 (t, J=6.4 Hz, 2H), 3.41 (d, J=5.6 Hz, 2H), 3.44 (d,J=5.2 Hz, 2H), 4.26 (t, J=5.2 Hz, 2H), 6.84 (d, J=8.4 Hz, 1H), 7.49 (t,J=7.6 Hz, 2H), 7.58 (t, J=7.6 Hz, 1H), 7.81 (d, J=9.2 Hz, 2H), 8.05 (d,J=7.2 Hz, 2H); ESIMS found C₁₉H₁₈O₃ m/z 295.0 (M+H).

1-(Benzo[d][1,3]dioxol-5-yl)-4-(2-(trifluoromethyl)phenyl)butane-1,4-dione210

White solid (66 mg, 0.19 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.26 (t,J=6.4 Hz, 21-1), 3.40 (t, J=6.4 Hz, 2H), 6.05 (s, 2H), 6.87 (d, J=8 Hz,1H), 7.48 (d, J=1.6 Hz, 1H), 7.57 (t, 1H), 7.60-7.68 (m, 2H), 7.68-7.79(m, 2H); ESIMS found C₁₈H₁₃F₃O₄ m/z 350.9 (M+H).

1-(Benzo[d][1,3]dioxol-5-yl)-4-(2-fluorophenyl)butane-1,4-dione 213

White solid (10 mg, 0.03 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.32-3.40(m, 2H), 3.40-3.50 (m, 2H), 6.06 (s, 2H), 6.88 (d, J=8.03 Hz, 1H), 7.17(dd, J=11.17, 8.41 Hz, 1H), 7.24 (t, J=7.65 Hz, 1H), 7.49 (d, J=1.51 Hz,1H), 7.50-7.59 (m, 1H), 7.66 (dd, J=8.16, 1.63 Hz, 1H), 7.91 (td,J=7.65, 1.76 Hz, 1H); ESIMS found C₁₇H₁₃FO₄ m/z 301.0 (M+H).

1-(Benzo[d][1,3]dioxol-5-yl)-4-(3-fluorophenyl)butane-1,4-dione 214

White solid (30 mg, 0.10 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.41 (s,4H), 6.06 (s, 2H), 6.89 (d, J=8.4 Hz, 1H), 7.29 (dt, J=2.4 Hz, J=7.2 Hz,1H), 7.43-7.53 (m, 2H), 7.67 (dd, J=1.2 Hz, J=8 Hz, 1H), 7.70 (d, J=8.4Hz, 1H), 7.83 (d, J=8 Hz, 111); ESIMS found C₁₇H₁₃FO₄ m/z 323.0 (M+H).

1-(Benzo[d][1,3]dioxol-5-yl)-4-(2-methoxyphenyl)butane-1,4-dione 216

White solid (30 mg, 0.10 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.34 (t,J=6.4 Hz, 2H), 3.45 (t, J=6.4 Hz, 2H), 3.93 (s, 3H), 6.05 (s, 2H), 6.87(d, J=8 Hz, 1H), 6.96-7.06 (m, 2H), 7.48 (t, 1H), 7.50 (d, J=1.2 Hz,1H), 7.66 (dd, J=1.6 Hz, J=8 Hz, 1H), 7.77 (dd, J=1.6 Hz, J=8 Hz, 1H);ESIMS found C₁₈H₁₆O₅ m/z 313.0 (M+H).

1-(Benzo[d][1,3]dioxol-5-yl)-4-(3-methoxyphenyl)butane-1,4-dione 217

White solid (30 mg, 0.10 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.35-3.41(m, 2H), 3.41-3.47 (m, 2H), 3.87 (s, 3H), 6.06 (s, 2H), 6.88 (d, J=8.28Hz, 1H), 7.13 (ddd, J=8.16, 2.64, 1.00 Hz, 1H), 7.40 (t, J=7.91 Hz, 1H),7.50 (d, J=1.52 Hz, 1H), 7.55 (dd, J=2.52, J=1.52 Hz, 1H), 7.64 (dt,J=7.84, 1.10 Hz, 1H), 7.68 (dd, J=8.03, 1.76 Hz, 1H); ESIMS foundC₁₈H₁₆O₅ m/z 313.0 (M+H).

1-(Benzo[d][1,3]dioxol-5-yl)-4-phenylbutane-1,4-dione 222

White solid (48 mg, 0.17 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.39 (t,J=5.6 Hz, 2H), 3.45 (t, J=5.6 Hz, 2H), 6.06 (s, 2H), 6.88 (d, J=8.4 Hz,1H), 7.43-7.53 (m, 3H), 7.58 (t, J=7.6 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H),8.04 (d, J=7.6 Hz, 2H); ESIMS found C₁₇H₁₄O₄ m/z 283.0 (M+H).

1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-4-(pyridin-2-yl)butane-1,4-dione232

White solid (11 mg, 0.03 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.44 (t,J=6 Hz, 2H), 3.73 (t, J=6 Hz, 2H), 7.18 (d, J=8.4 Hz, 1H), 7.53 (t, J=4Hz, 1H), 7.78 (s, 1H), 7.83-7.95 (m, 2H), 8.07 (d, J=8 Hz, 1H), 8.75 (d,J=4 Hz, 1H); ESIMS found C₁₆H₁₁F₂NO₄ m/z 320.1 (M+H).

1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-4-phenylbutane-1,4-dione 235

White solid (20 mg, 0.06 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.43 (t,J=6 Hz, 2H), 3.50 (t, J=6 Hz, 2H), 7.19 (d, J=8.4 Hz, 1H), 7.51 (t,J=7.6 Hz, 2H), 7.62 (t, J=7.6 Hz, 1H), 7.78 (d, J=2 Hz, 1H), 7.91 (dd,J=1.5 Hz, J=8.4 Hz, 1H), 8.06 (d, J=7.2 Hz, 2H); ESIMS found C₁₇H₁₂F₂O₄m/z 318.9 (M+H).

1-(2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)-4-(4-(trifluoromethyl)phenyl)butane-1,4-dione238

White solid (14 mg, 0.04 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.43 (t,J=6 Hz, 2H), 3.51 (t, J=6 Hz, 2H), 4.34 (t, J=4 Hz, 2H), 4.42 (t, J=4Hz, 2H), 6.91 (t, J=8 Hz, 1H), 7.06 (dd, J=1.2 Hz, J=8 Hz, 1H), 7.38(dd, J=1.6 Hz, J=8 Hz, 1H), 7.77 (d, J=8 Hz, 2H), 8.16 (d, J=8.4 Hz,2H); ESIMS found C₁₉H₁₅F₃O₄ m/z 365.0 (M+H).

1-(2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)-4-(3-fluorophenyl)butane-1,4-dione240

White solid (79 mg, 0.25 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.40 (t,J=6 Hz, 2H), 3.48 (t, J=6 Hz, 2H), 4.34 (dd, J=4 Hz, J=6 Hz, 2H), 4.41(dd, J=4 Hz, J=6 Hz, 2H), 6.91 (t, J=7.6 Hz, 1H), 7.05 (dd, J=1.6 Hz,J=8 Hz, 1H), 7.26-7.32 (m, 1H), 7.38 (dd, J=1.6 Hz, J=8 Hz, 1H), 7.48(dd, J=7.6 Hz, J=8.8 Hz, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.85 (d, J=7.6 Hz,1H); ESIMS found C₁₈H₁₅FO₄ m/z 314.9 (M+H).

1-(2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)-4-(2-methoxyphenyl)butane-1,4-dione242

White solid (40 mg, 0.12 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.29-3.46(m, 411), 3.93 (s, 3H), 4.25-4.35 (m, 2H), 4.35-4.43 (m, 2H), 6.88 (t,J=8 Hz, 111), 6.94-7.07 (m, 314), 3.34 (dd, J=1.6 Hz, J=8 Hz, 1H), 7.46(dt, J=1.6 Hz, J=7.6 Hz, 1H), 7.76 (dd, J=1.6 Hz, J=7.6 Hz, 1H); ESIMSfound C₁₉H₁₈O₅ m/z 327.0 (M+H).

1-(2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)-4-phenylbutane-1,4-dione 248

White solid (28 mg, 0.10 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.39-3.54(m, 411), 4.28-4.35 (m, 2H), 4.35-4.44 (m, 2H), 6.89 (t, J=7.6 Hz, 1H),7.03 (dd, J=2.4 Hz, J=7.6 Hz, 1H), 7.36 (dd, J=1.2 Hz, J=7.6 Hz, 1H),7.48 (t, J=7.6 Hz, 2H), 7.58 (t, J=7.6 Hz, 1H), 8.04 (dd, J=1.2 Hz, J=8Hz, 2H); ESIMS found C₁₈H₁₆O₄ m/z 297.0 (M+H).

1-(Benzofuran-5-yl)-4-(2-(trifluoromethyl)phenyl)butane-1,4-dione 275

Oil (27 mg, 0.08 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.34 (t, J=6 Hz,2H), 3.57 (t, J=6 Hz, 2H), 6.89 (d, J=1.2 Hz, 1H), 7.60 (t, J=8.4 Hz,2H), 7.68 (t, J=7.2 Hz, 1H), 7.71-7.74 (m, 2H), 7.78 (t, J=7.2 Hz, 1H),8.05 (dd, J=1.6 Hz, J=8.4 Hz, 1H), 8.36 (s, 1H); ESIMS found C₁₉H₁₃F₃O₃m/z 346.9 (M+H).

1-(Benzofuran-5-yl)-4-(2-fluorophenyl)butane-1,4-dione 278

White solid (34 mg, 0.11 mmol). ¹H NMR (DMSO-d₆, 400 MHz) 6 ppm3.34-3.46-3.52 (m, 2H), 7.12 (t, J=1.50 Hz, 1H), 7.32-7.44 (m, 2H),7.65-7.71 (m, 1H), 7.73 (d, J=8.78 Hz, 1H), 7.86 (td, J=7.65, 1.76 Hz,1H), 7.99 (dd, J=8.78, 1.76 Hz, 1H), 8.13 (d, J=2.26 Hz, 1H), 7.12 (d,J=1.50 Hz, 1H); ESIMS found C₁₈H₁₃FO₃ m/z 297.0 (M+H).

1-(Benzofuran-5-yl)-4-(2-methoxyphenyl)butane-1,4-dione 281

White solid (50 mg, 0.16 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.45-3.53(m, 4H), 3.94 (s, 3H), 6.88 (dd, J=2.26, 0.75 Hz, 1H), 6.95-7.08 (m,2H), 7.49 (ddd, J=8.34, 7.34, 1.88 Hz, 1H), 7.57 (d, J=8.53 Hz, 1H),7.70 (d, J=2.26 Hz, 1H), 7.79 (dd, J=7.65, 1.88 Hz, 1H), 8.05 (dd,J=8.78, 1.76 Hz, 1H), 8.36 (d, J=1.76 Hz, 1H); ESIMS found C₁₉H₁₆O₄ m/z309.1 (M+H).

1-(Benzofuran-5-yl)-4-phenylbutane-1,4-dione 287

White solid (16 mg, 0.06 mmol). ¹H NMR (DMSO-d₆, 400 MHz) 6 ppm3.41-3.47 (m, 2H) 3.47-3.52 (m, 2H) 7.13 (dd, J=2.13 Hz, J=0.88 Hz, 1H)7.57 (t, J=7.56 Hz, 2H) 7.67 (t, J=6.99 Hz, 1H) 7.74 (d, J=8.78 Hz, 1H)8.00 (dd, J=8.53 Hz, J=1.76 Hz, 1H) 8.02-8.06 (m, 2H) 8.14 (d, J=2.26Hz, 1H) 8.44 (d, J=1.76 Hz, 1H); ESIMS found C₁₈H₁₄O₃ m/z 279.1 (M+H).

1-(Benzo[d]oxazol-5-yl)-4-(2-(trifluoromethyl)phenyl)butane-1,4-dione288

White solid (15 mg, 0.04 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.31-3.38(m, 2H), 3.54-3.60 (m, 2H), 7.59 (t, J=7.66 Hz, 1H), 7.66-7.71 (m, 2H),7.74 (d, J=7.78 Hz, 1H), 7.79 (d, J=7.53 Hz, 1H), 8.15 (dd, J=1.6 Hz,J=8.31 Hz, 1H), 8.21 (s, 1H), 8.50 (d, J=1.51 Hz, 1H); ESIMS foundC₁₈H₁₂F₃NO₃ m/z 348.1 (M+H).

1-(Benzo[d]oxazol-5-yl)-4-(2-fluorophenyl)butane-1,4-dione 291

White solid (12 mg, 0.04 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.45-3.59(m, 4H), 7.18 (ddd, J=11.23, 8.34, 1.00 Hz, 1H), 7.22-7.27 (m, 1H),7.49-7.60 (m, 1H), 7.68 (d, J=8.78 Hz, 1H), 7.92 (td, J=7.65, 1.76 Hz,1H), 8.17 (dd, J=8.56, 1.76 Hz, 1H), 8.20 (s, 1H), 8.51 (d, J=1.25 Hz,1H); ESIMS found C₁₇H₁₂FNO₃ m/z 298.1 (M+H).

1-(Benzo[d]oxazol-5-yl)-4-(3-fluorophenyl)butane-1,4-dione 292

White solid (28 mg, 0.09 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.45-3.52(m, 2H), 3.54-3.61 (m, 2H), 7.31 (dt, J=1.00 Hz, J=8.28 Hz, 1H), 7.50(td, J=8.03 Hz, J=5.52 Hz, 1H), 7.70 (d, J=8.53 Hz, 1H), 7.72-7.78 (m,1H), 7.87 (dt, J=7.78 Hz, J=1.13 Hz, 1H), 8.18 (d, J=8.73 Hz, 1H), 8.21(s, 1H), 8.53 (d, J=1.51 Hz, 1H); ESIMS found C₁₇H₁₂FNO₃ m/z 298.0(M+H).

1-(Benzo[d]oxazol-5-yl)-4-(2-methoxyphenyl)butane-1,4-dione 294

White solid (10 mg, 0.03 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.44-3.56(m, 4H), 3.95 (s, 3H), 6.95-7.08 (m, 2H), 7.49 (td, J=7.80, 1.50 Hz,1H), 7.67 (d, J=8.53 Hz, 1H), 7.79 (dd, J=7.65, 1.63 Hz, 1H), 8.16 (dd,J=8.80, 1.50 Hz, 1H), 8.19 (s, 1H), 8.51 (d, J=1.00 Hz, 1H); ESIMS foundC₁₈H₁₅NO₄ m/z 310.1 (M+H).

1-(Benzo[d]oxazol-5-yl)-4-phenylbutane-1,4-dione 300

White solid (50 mg, 0.18 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.48-3.59(m, 4H), 7.46-7.55 (m, 2H), 7.60 (tt, J=1.24 Hz, J=7.52 Hz, 1H), 7.68(d, J=8.53 Hz, 1H), 8.03-8.09 (m, 2H), 8.17 (dd, J=8.78 Hz, J=1.76 Hz,1H), 8.20 (s, 1H), 8.53 (d, J=1.51 Hz, 1H); ESIMS found C₁₇H₁₃NO₃ m/z280.0 (M+H).

1-(Benzo[b]thiophen-5-yl)-4-(2-(trifluoromethyl)phenyl)butane-1,4-dione301

White solid (83 mg, 0.23 mmol). ¹H NMR (DMSO-d₆, 400 MHz) 6 ppm3.30-3.37 (m, 2H), 3.48-3.57 (m, 2H), 7.65 (d, J=5.27 Hz, 1H), 7.75 (t,J=7.61 Hz, 1H), 7.85 (t, J=7.76 2H), 7.91 (d, J=5.27 Hz, 1H), 7.95-8.01(m, 2H), 8.17 (d, J=8.53 Hz, 1H), 8.65 (d, J=1.25 Hz, 1H); ESIMS foundC₁₉H₁₃F₃O₂S m/z 362.9 (M+H).

1-(Benzo[b]thiophen-5-yl)-4-(2-methoxyphenyl)butane-1,4-dione 307

Brown solid (20 mg, 0.06 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.52 (s,2H), 3.95 (s, 2H), 6.97-7.09 (m, 2H), 7.43-7.52 (m, 2H), 7.54 (d, J=5.52Hz, 1H), 7.79 (dd, J=7.78, 1.76 Hz, 1H), 7.96 (d, J=8.52 Hz, 1H), 8.02(dd, J=8.52, 1.24 Hz, 1H), 8.54 (d, J=1.00 Hz, 1H); ESIMS foundC₁₉H₁₆O₃S m/z 324.9 (M+H).

1-(Benzo[b]thiophen-5-yl)-4-(pyridin-2-yl)butane-1,4-dione 310

White solid (20 mg, 0.07 mmol). ¹H NMR (DMSO-d₆, 400 MHz) 6 ppm3.50-3.55 (m, 2H), 3.55-3.61 (m, 2H), 7.63 (d, J=5.52 Hz, 1H), 7.69(ddd, J=1.52 Hz, J=5.52 Hz, J=7.52 Hz, 1H), 7.89 (d, J=5.52 Hz, 1H),7.92-7.98 (m, 2H), 8.02 (dt, J=1.76, J=7.67 Hz, 1H), 8.15 (d, J=8.53 Hz,1H), 8.62 (d, J=1.51 Hz, 1H), 8.77 (d, J=4.79 Hz, 1H); ESIMS foundC₁₇H₁₃NO₂S m/z 296.1 (M+H).

1-(Benzo[b]thiophen-5-yl)-4-phenylbutane-1,4-dione 313

White solid (105 mg, 0.36 mmol). ¹H NMR (DMSO-d₆, 400 MHz) 6 ppm3.41-3.48 (m, 2H), 3.48-3.55 (m, 2H), 7.51-7.61 (m, 2H), 7.62-7.71 (m,2H), 7.91 (d, J=5.52 Hz, 1H), 7.96 (dd, J=8.53 Hz, J=1.51 Hz, 1H), 8.03(d, J=7.36 Hz, 2H), 8.16 (d, J=8.53 Hz, 1H), 8.64 (d, J=1.51 Hz, 1H);ESIMS found C₁₈H₁₄O₂S m/z 295.1 (M+H).

1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-4-(o-tolyl)butane-1,4-dione 342

White solid (15 mg, 0.05 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 2.52 (s,3H), 3.35 (t, J=5.2 Hz, 2H), 3.39 (t, J=5.2 Hz, 2H), 4.31 (d, J=5.2 Hz,2H), 4.35 (d, J=5.2 Hz, 2H), 6.95 (AA′BB′quartet, 1H), 7.26-7.35 (m,2H), 7.40 (t, J=7.6 Hz, 1H), 7.56-7.61 (m, 2H), 7.83 (d, J=7.2 Hz, 1H);ESIMS found C₁₉H₁₈O₄ m/z 311.1 (M+H).

1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-4-(m-tolyl)butane-1,4-dione 343

White solid (13 mg, 0.04 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 2.43 (s,3H), 3.39 (t, J=4.8 Hz, 2H), 3.43 (t, J=4.8 Hz, 2H), 4.30 (d, J=5.2 Hz,2H), 4.33 (d, J=5.2 Hz, 2H), 6.93 (AA′BB′quartet, 1H), 7.34-7.42 (m,2H), 7.56-7.62 (m, 2H), 7.84 (d, J=7.6 Hz, 2H); ESIMS found C₁₉H₁₈O₄ m/z311.1 (M+H).

1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-4-(p-tolyl)butane-1,4-dione 344

White solid (26 mg, 0.08 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 2.43 (s,3H), 3.35-3.45 (m, 4H), 4.30 (d, J=5.6 Hz, 2H), 4.33 (d, J=5.6 Hz, 2H),6.93 (AA′BB′quartet, 1H), 7.26-7.33 (m, 2H), 7.57-7.63 (m, 2H), 7.94 (d,J=8 Hz, 2H); ESIMS found C₁₉H₁₈O₄ m/z 311.1 (M+H).

1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-4-(pyrimidin-5-yl)butane-1,4-dione345

White solid (9 mg, 0.03 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.40 (t,J=6 Hz, 2H), 3.48 (t, J=6 Hz, 2H), 4.28-4.39 (m, 4H), 6.96(AA′BB′quartet, 1H), 7.55-7.62 (m, 2H), 9.34 (s, 2H), 9.41 (s, 1H);ESIMS found C₁₆H₁₄N₂O₄ m/z 299.0 (M+H).

1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-4-(furan-2-yl)butane-1,4-dione346

White solid (42 mg, 0.15 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.29 (t,J=6 Hz, 2H), 3.38 (t, J=6 Hz, 2H), 4.26-4.31 (m, 2H), 4.31-4.36 (m, 2H),6.56 (dd, J=2 Hz, J=5.2 Hz, 1H), 6.92 (AA′BB′quartet, 1H), 7.25-7.29 (m,1H), 7.55-7.64 (m, 2H), 7.61 (s, 1H); ESIMS found C₁₆H₁₄O₅ m/z 287.1(M+H).

1-(Chroman-6-yl)-4-(o-tolyl)butane-1,4-dione 358

Yellow solid (28 mg, 0.09 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 1.99-2.08(m, 2H), 2.51 (s, 3H), 2.84 (t, J=6.53 Hz, 2H), 3.31-3.36 (m, 2H),3.36-3.42 (m, 2H), 4.26 (t, J=5.28 Hz, 2H), 6.84 (d, J=8.28 Hz, 1H),7.24-7.32 (m, 2H), 7.39 (td, J=7.50, 1.52 Hz, 1H), 7.77-7.84 (m, 3H);ESIMS found C₂₀H₂₀O₃ m/z 309.2 (M+H).

1-(Chroman-6-yl)-4-(thiophen-2-yl)butane-1,4-dione 364

Yellow solid (18 mg, 0.06 mmol). ¹H NMR (DMSO-d₆, 400 MHz) 8 ppm 1.94(quin, J=5.02 Hz, 2H), 2.80 (t, J=6.15 Hz, 2H), 3.31 (s, 4H), 3.36 (s,411), 4.21 (t, J=4.76 Hz, 2H), 6.83 (d, J=8.53 Hz, 1H), 7.26 (t, J=4.27Hz, 1H), 7.73 (d, J=8.53 Hz, 1H), 7.77 (s, 1H), 8.00 (d, J=4.77 Hz, 1H),8.04 (d, J=3.76 Hz, 1H); ESIMS found C₁₇H₁₆O₃S m/z 301.1 (M+H).

1-(Chroman-6-yl)-4-(furan-2-yl)butane-1,4-dione 365

White solid (11 mg, 0.04 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 2.04(quin, J=5.00 Hz, 2H), 2.84 (t, J=6.40 Hz, 2H), 3.26-3.32 (m, 2H),3.35-3.42 (m, 2H), 4.25 (t, J=5.04 Hz, 2H), 6.56 (dd, J=3.51, 1.76 Hz,1H), 6.83 (d, J=8.28 Hz, 1H), 7.25-7.28 (m, 1H), 7.61 (d, J=0.75 Hz,1H), 7.74-7.81 (m, 2H); ESIMS found C₁₇H₁₆O₄ m/z 285.2 (M+H).

1-(Benzo[d][1,3]dioxol-5-yl)-4-(o-tolyl)butane-1,4-dione 368

White solid (66 mg, 0.22 mmol). ¹H NMR (DMSO-d₆, 400 MHz) 6 ppm 2.37 (s,3H), 3.24 (t, J=6 Hz, 2H), 3.27-3.35 (m, 2H), 6.14 (s, 2H), 7.06 (d, J=8Hz, 1H), 7.30 (t, J=7.2 Hz, 1H), 7.35 (d, 1H), 7.43 (t, 1H), 7.48 (s,1H), 7.68 (dd, J=1.6 Hz, J=8.4 Hz, 1H), 7.84 (d, J=7.2 Hz, 1H); ESIMSfound C₁₈H₁₆O₄ m/z 297.0 (M+H).

1-(Benzo[d][1,3]dioxol-5-yl)-4-(thiophen-2-yl)butane-1,4-dione 374

White solid (23 mg, 0.08 mmol). ¹H NMR (DMSO-d₆, 400 MHz) 6 ppm3.30-3.36 (m, 4H), 6.14 (s, 2H), 7.06 (d, J=8.03 Hz, 1H), 7.27 (dd,J=5.02, 3.76 Hz, 1H), 7.46 (d, J=1.51 Hz, 1H), 7.66 (dd, J=8.28, 1.76Hz, 1H), 8.00 (dd, J=5.02, 1.00 Hz, 11-1), 8.04 (dd, J=3.76, 1.25 Hz,1H); ESIMS found C₁₅H₁₂O₄S m/z 288.9 (M+H).

1-(Benzo[d][1,3]dioxol-5-yl)-4-(furan-2-yl)butane-1,4-dione 375

White solid (10 mg, 0.04 mmol). ¹H NMR (DMSO-d₆, 400 MHz) 6 ppm3.13-3.20 (m, 2H), 3.28-3.35 (m, 2H), 6.14 (s, 2H), 6.73 (dd, J=3.51,1.76 Hz, 1H), 7.05 (d, J=8.03 Hz, 1H), 7.46 (d, J=1.76 Hz, 1H), 7.49 (d,J=3.86 Hz, 1H), 7.66 (dd, J=8.16, 1.63 Hz, 1H), 8.00 (d, J=1.00 Hz, 1H);ESIMS found C₁₅H₁₂O₅ m/z 273.0 (M+H).

1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-4-(m-tolyl)butane-1,4-dione 379

White solid (308.2 mg, 0.98 mmol). ¹H NMR (CDCl₃, 400 MHz) 6 ppm 2.43(s, 3H), 3.41 (t, J=5.6 Hz, 2H), 3.47 (t, J=5.6 Hz, 2H), 7.17 (d, J=8.4Hz, 1H), 7.39 (q, J=8.8 Hz, 2H), 7.77 (d, J=1.6 Hz, 1H), 7.84 (d, J=6.8Hz, 2H), 7.90 (dd, J=1.6 Hz, J=8.4 Hz, 1H); ESIMS found C₁₈H₁₄F₂O₄ m/z333.1 (M+H).

1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-4-(furan-2-yl)butane-1,4-dione385

White solid (11 mg, 0.04 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.33 (t,J=6 Hz, 2H), 3.39 (t, J=6 Hz, 2H), 6.57 (dd, J=2.5 Hz, J=3.5 Hz, 1H),7.15 (d, J=7.6 Hz, 1H), 7.23-7.31 (m, 1H), 7.62 (s, 1H), 7.74 (d, J=1.6Hz, 1H), 7.86 (dd, J=1.6 Hz, J=7.6 Hz, 1H); ESIMS found C₁₅H₁₀F₂O₅ m/z309.1 (M+H).

1-(3,4-Dimethoxyphenyl)-4-(m-tolyl)butane-1,4-dione 425

White solid (27 mg, 0.09 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 2.43 (s,3H), 3.45 (s, 4H), 3.95 (s, 3H), 3.97 (s, 3H), 6.93 (d, J=8.53 Hz, 1H),7.35-7.44 (m, 2H), 7.58 (d, J=2.01 Hz, 1H), 7.72 (dd, J=8.53, 2.01 Hz,1H), 7.83-7.89 (m, 2H); ESIMS found C₁₉H₂₀O₄ m/z 313.1 (M+H).

1-(3,4-Dimethoxyphenyl)-4-(p-tolyl)butane-1,4-dione 426

White solid (34 mg, 0.11 mmol). 1H NMR (CDCl3, 400 MHz) δ ppm 2.43 (s,3H), 3.44 (s, 411), 3.94 (s, 3H), 3.97 (s, 3H), 6.93 (d, J=8.53 Hz, 1H),7.29 (d, J=8.03 Hz, 2H), 7.57 (d, J=2.01 Hz, 1H), 7.72 (dd, J=8.41, 2.13Hz, 1H), 7.95 (d, J=7.71 Hz, 2H); ESIMS found C19H20O4 m/z 313.0 (M+H).

1-(2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)-4-(furan-2-yl)butane-1,4-dione442

White solid (23 mg, 0.08 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.26 (t,J=6.4 Hz, 2H), 3.44 (t, J=6.4 Hz, 2H), 4.27-4.35 (m, 2H), 4.35-4.42 (m,2H), 6.56 (dd, J=1.6 Hz, J=3.6 Hz, 1H), 6.88 (t, J=8 Hz, 1H), 7.03 (dd,J=1.6 Hz, J=8 Hz, 1H), 7.24-7.29 (m, 1H), 7.35 (dd, J=1.6 Hz, J=7.6 Hz,1H), 7.61 (s, 1H); ESIMS found C₁₆H₁₄O₅ m/z 286.9 (M+H).

1-(Benzofuran-5-yl)-4-(o-tolyl)butane-1,4-dione 455

White solid (12 mg, 0.04 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 2.52 (s,3H), 3.35-3.43 (m, 2H), 3.51-3.57 (m, 2H), 6.88 (dd, J=2.26, 0.75 Hz,1H), 7.24-7.34 (m, 2H), 7.40 (td, J=7.52, 1.24 Hz, 1H), 7.57 (d, J=8.53Hz, 1H), 7.71 (d, J=2.26 Hz, 1H), 7.84 (dd, J=7.65, 1.13 Hz, 1H), 8.05(dd, J=8.78, 1.76 Hz, 1H), 8.36 (d, J=1.76 Hz, 1H); ESIMS found C₁₉H₁₆O₃m/z 293.0 (M+H).

1-(Benzofuran-5-yl)-4-(m-tolyl)butane-1,4-dione 456

White solid (19 mg, 0.07 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 2.44 (s,3H), 3.50 (d, J=5.2 Hz, 2H), 3.53 (d, J=5.2 Hz, 2H), 6.88 (s, 1H), 7.39(d, J=7.2 Hz, 2H), 7.58 (d, J=8.4 Hz, 1H), 7.71 (d, J=2 Hz, 1H), 7.86(d, J=6.8 Hz, 2H), 8.06 (d, J=8.4 Hz, 1H), 8.37 (s, 1H); ESIMS foundC₁₉H₁₆O₃ m/z 293.1 (M+H).

1-(Benzofuran-5-yl)-4-(p-tolyl)butane-1,4-dione 457

White solid (73 mg, 0.25 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 2.43 (s,3H), 3.45-3.51 (m, 2H), 3.51-3.57 (m, 2H), 6.89 (dd, J=2.13, 0.88 Hz,1H), 7.29 (d, J=8.03 Hz, 2H), 7.57 (d, J=8.53 Hz, 1H), 7.71 (d, J=2.26Hz, 1H), 7.96 (d, J=7.72 Hz, 2H), 8.06 (dd, J=8.66, 1.88 Hz, 1H), 8.37(d, J=1.76 Hz, 1H); ESIMS found C₁₉H₁₆O₃ m/z 293.0 (M+H).

1-(Benzofuran-5-yl)-4-(furan-2-yl)butane-1,4-dione 462

White solid (25 mg, 0.09 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.35 (t,J=6.4 Hz, 2H), 3.53 (t, J=6.4 Hz, 2H), 6.57 (dd, J=2 Hz, J=3.6 Hz, 1H),6.88 (d, J=1.6 Hz, 1H), 7.24-7.31 (m, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.62(s, 1H), 7.71 (d, J=2 Hz, 1H), 8.03 (dd, J=1.2 Hz, J=8.8 Hz, 1H), 8.34(d, J=1.2 Hz, 1H); ESIMS found C₁₆H₁₂O₄ m/z 269.2 (M+H).

1-(Benzo[d]oxazol-5-yl)-4-(o-tolyl)butane-1,4-dione 485

White solid (15 mg, 0.05 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 2.52 (s,3H), 3.38-3.44 (m, 2H), 3.51-3.57 (m, 2H), 7.2-7.35 (m, 2H), 7.40 (dt,J=1.48 Hz, J=7.52 Hz, 1H), 7.68 (d, J=8.33 Hz, 1H), 7.85 (dd, J=7.53 Hz,J=1.25 Hz, 1H), 8.17 (dd, J=1.76 Hz, J=8.63 Hz, 1H), 8.20 (s, 1H), 8.52(d, J=1.51 Hz, 1H); ESIMS found C₁₈H₁₅NO₃ m/z 294.2 (M+H).

1-(2-Fluorophenyl)-4-(pyridin-2-yl)butane-1,4-dione 538

White solid (30 mg, 0.12 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.50 (t,J=6 Hz, 2H), 3.70 (t, J=6 Hz, 2H), 7.18 (t, J=8.8 Hz, 1H), 7.27 (t,J=7.2 Hz, 1H), 7.45-7.62 (m, 2H), 7.86 (dt, J=1.6 Hz, J=7.6 Hz, 1H),7.93 (dt, J=2 Hz, 1H), 8.07 (d, J=8 Hz, 1H), 8.74 (d, J=4 Hz, 1H); ESIMSfound C₁₅H₁₂FNO₂ m/z 258.0 (M+H).

1-(Pyridin-2-yl)-4-(2-(trifluoromethyl)phenyl)butane-1,4-dione 541

Oil (41 mg, 0.13 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.31 (t, J=6.4 Hz,2H), 3.73 (t, J=6.4 Hz, 2H), 7.50 (t, J=4.8 Hz, 1H), 7.58 (t, J=7.6 Hz,1H), 7.66 (t, J=7.6 Hz, 1H), 7.70-7.77 (m, 2H), 7.85 (dt, J=1.2 Hz,J=7.6 Hz, 1H), 8.05 (d, J=8 Hz, 111), 8.72 (d, J=4.4 Hz, 1H); ESIMSfound C₁₆H₁₂F₃NO₂ m/z 307.9 (M+H).

1-(Pyridin-2-yl)-4-(o-tolyl)butane-1,4-dione 544

Oil (39 mg, 0.15 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 2.51 (s, 3H), 3.37(t, J=6.4 Hz, 2H), 3.69 (t, J=6.4 Hz, 2H), 7.21-7.34 (m, 2H), 7.38 (dt,J=1 Hz, J=7.2 Hz, 1H), 7.49 (dd, 1H), 7.76-7.90 (m, 2H), 8.05 (d, J=7.6Hz, 1H), 8.72 (d, J=4.4 Hz, 111); ESIMS found C₁₆H₁₅NO₂ m/z 254.0 (M+H).

1-(2-Methoxyphenyl)-4-(pyridin-2-yl)butane-1,4-dione 547

White solid (40 mg, 0.15 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.47 (t,J=6.8 Hz, 2H), 3.64 (t, J=6.8 Hz, 2H), 3.93 (s, 3H), 6.94-7.07 (m, 2H),7.41-7.53 (m, 2H), 7.77 (dd, 1H), 7.84 (dt, J=1.2 Hz, J=8 Hz, 1H), 8.05(d, J=8 Hz, 1H), 8.71 (d, J=4.4 Hz, 1H); ESIMS found C₁₆H₁₅NO₃ m/z 270.1(M+H).

1-(Furan-2-yl)-4-(pyridin-2-yl)butane-1,4-dione 554

White solid (11 mg, 0.05 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.32 (t,J=6.8 Hz, 2H), 3.69 (t, J=6.8 Hz, 2H), 6.56 (dd, J=1.6 Hz, J=3.2 Hz,1H), 7.23-7.30 (m, 1H), 7.50 (t, J=6.4 Hz, 1H), 7.61 (s, 1H), 7.85 (dt,J=1.6 Hz, J=7.6 Hz, 1H), 8.05 (d, J=8.4 Hz, 1H), 8.71 (d, J=4.4 Hz, 1H);ESIMS found C₁₃H₁₁NO₃ m/z 230.1 (M+H).

1-(2-Fluorophenyl)-4-(thiophen-2-yl)butane-1,4-dione 557

White solid (15 mg, 0.06 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.35-3.42(m, 2H), 3.42-3.50 (m, 2H), 7.12-7.20 (m, 2H), 7.24 (td, J=7.80 Hz,J=1.00 Hz, 1H), 7.49-7.57 (m, 1H), 7.65 (dd, J=4.89 Hz, J=1.13 Hz, 1H),7.83 (dd, J=3.89 Hz, J=1.13 Hz, 1H), 7.90 (td, J=7.59 Hz, J=1.88 Hz,1H); ESIMS found C₁₄H₁₁FO₂S m/z 262.9 (M+H).

1-(Thiophen-2-yl)-4-(2-(trifluoromethyl)phenyl)butane-1,4-dione 559

White solid (69 mg, 0.22 mmol). ¹H NMR (DMSO-d₆, 400 MHz) 6 ppm3.25-3.31 (m, 2H), 3.35-3.40 (m, 2H), 7.27 (dd, J=4.89, 3.89 Hz, 1H),7.73 (t, J=7.80 Hz, 1H), 7.80-7.88 (m, 2H), 7.92 (d, J=7.56 Hz, 1H),8.03 (dd, J=5.04, 1.00 Hz, 1H), 8.06 (dd, J=3.76, 1.00 Hz, 1H); ESIMSfound C₁₅H₁₁F₃O₂S m/z 312.9 (M+H).

1-(Thiophen-2-yl)-4-(o-tolyl)butane-1,4-dione 560

White solid (38 mg, 0.15 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 2.53 (s,3H), 3.34-3.47 (m, 4H), 7.18 (t, J=4.4 Hz, 1H), 7.24-7.35 (m, 2H), 7.41(t, J=7.6 Hz, 1H), 7.67 (d, J=4.8 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.85(d, J=2.8 Hz, 1H); ESIMS found C₁₅H₁₄O₂S m/z 259.0 (M+H).

1-(2-Methoxyphenyl)-4-(thiophen-2-yl)butane-1,4-dione 562

White solid (60 mg, 0.22 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.36 (t,J=6.8 Hz, 2H), 3.47 (t, J=6.8 Hz, 2H), 3.94 (s, 3H), 6.95-7.07 (m, 2H),7.16 (dt, J=5.2 Hz, 1H), 7.48 (dt, 1H), 7.64 (d, J=4 Hz, 1H), 7.78 (dd,J=5.6, J=7.6 Hz, 1H), 7.83 (dd, 1H); ESIMS found C₁₅H₁₄O₃S m/z 275.0(M+H).

Example 2

Preparation of 1-(1H-indol-5-yl)-4-phenylbutane-1,4-dione (261) isdepicted below in Scheme 16.

Step 1-2

To a well stirred solution of 3-(dimethylamino)-1-phenylpropan-1-one(XXXIV) (120 mg, 0.678 mmol, 1.0 eq) in 1,4-dioxane (3 mL) was addedtert-butyl 5-formyl-1H-indole-1-carboxylate (LXXV)(166 mg, 0.678 mmol,1.0 eq), 3-ethyl-5-(2-hydroxyeth-yl)-4-methylthiazolium brominde (51 mg,0.203 mmol, 0.3 eq) and TEA (0.5 mL). The reaction mixture was refluxedfor 16 h. TLC analysis (PE:EtOAc, 3:1) showed the reaction was complete.The solution was cooled to room temperature and diluted with water (20mL). The product was extracted with EtOAc (3×30 mL). The combinedorganic layers was dried over anhydrous Na₂SO₄, filled and concentratedunder reduced pressure to give crude tert-butyl5-(4-oxo-4-phenylbutanoyl)-1H-indole-1-carboxylate (LXXIX) (52 mg) as awhite solid. The crude product was dissolved in methanol (2 mL).Anhydrous sodium carbonate (144 mg, 1.36 mmol, 2.0 eq) was added. Thenthe mixture was stirred at 60° C. for 3 h. The solid was filtered offand the residue was concentrated in vacuum to give1-(1H-indol-5-yl)-4-phenylbutane-1,4-dione (261) as a white solid. (42mg, 0.15 mmol, 22.3%)¹H NMR (DMSO-d₆, 400 MHz) δ ppm 3.41 (t, J=6.4 Hz,2H), 3.47 (t, J=6.4 Hz, 2H), 6.62 (s, 1H), 7.41-7.52 (m, 2H), 7.56 (t,J=7.6 Hz, 2H), 7.66 (t, 1H), 7.77 (d, J=8.4 Hz, 1H), 8.03 (d, J=7.2 Hz,2H), 8.37 (s, 1H), 11.46 (s, 1H); ESIMS found C₁₈H₁₅NO₂ m/z 278.0 (M+H).

The following compounds were prepared in accordance with the proceduredescribed in the above Example 2.

1-(1H-Indol-5-yl)-4-(2-(trifluoromethyl)phenyl)butane-1,4-dione 249

White solid (10 mg, 0.03 mmol). ¹H NMR (DMSO-d₆, 400 MHz) 6 ppm3.25-3.32 (m, 2H), 3.45-3.54 (m, 2H), 6.62-6.66 (m, 1H), 7.47-7.53 (m,2H), 7.72-7.77 (m, 1H), 7.79 (dd, J=8.66 Hz, J=1.63 Hz, 1H), 7.83-7.89(m, 2H), 7.99 (d, J=7.53 Hz, 1H), 8.38 (s, 1H), 11.49 (brs, 1H); ESIMSfound C₁₉H₁₄F₃NO₂ m/z 346.0 (M+H).

1-(2-Fluorophenyl)-4-(1H-indol-5-yl)butane-1,4-dione 252

White solid (10 mg, 0.03 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.41-3.51(m, 2H), 3.51-3.60 (m, 2H), 6.66 (s, 1H), 7.10-7.19 (m, 1H), 7.19-7.30(m, 2H), 7.41 (d, J=8.8 Hz, 1H), 7.47-7.58 (m, 1H), 7.83-7.96 (m, 2H),8.40 (s, 1H), 8.59 (brs, 1H); ESIMS found C₁₈H₁₄FNO₂ m/z 296.0 (M+H).

1-(1H-Indol-5-yl)-4-(2-methoxyphenyl)butane-1,4-dione 255

White solid (36 mg, 0.12 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.44-3.57(m, 4H), 3.94 (s, 3H), 6.69 (ddd, J=3.14, 2.01, 0.88 Hz, 1H), 6.97-7.01(m, 1H), 7.01-7.06 (m, 1H), 7.29 (dd, J=3.26, 2.51 Hz, 1H), 7.43 (d,J=8.30 Hz, 1H), 7.45-7.51 (m, 1H), 7.79 (dd, J=7.78, 1.76 Hz, 1H), 7.94(dd, J=8.66, 1.63 Hz, 1H), 8.38-8.46 (m, 2H); ESIMS found C₁₉H₁₇NO₃ m/z308.2 (M+H).

1-(1H-Indol-5-yl)-4-(pyridin-2-yl)butane-1,4-dione 258

White solid (10 mg, 0.04 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.56-3.65(m, 2H), 3.69-3.78 (m, 2H), 6.70 (ddd, J=3.20 Hz, J=2.07 Hz, J=1.00 Hz,1H), 7.31 (dd, J=3.14 Hz, J=2.38 Hz, 1H), 7.45 (d, J=8.53 Hz, 1H), 7.51(ddd, J=7.53 Hz, J=4.77 Hz, J=1.25 Hz, 1H), 7.87 (td, J=7.78 Hz, J=1.76Hz, 1H), 7.95 (dd, J=8.66 Hz, J=1.63 Hz, 1H), 8.09 (dt, J=7.84 Hz,J=1.10 Hz, 1H), 8.42-8.45 (m, 1H), 8.42-8.50 (brs, 1H), 8.71-8.78 (m,1H); ESIMS found C₁₇H₁₄N₂O₂ m/z 279.1 (M+H).

1-(1H-Benzo[d]imidazol-5-yl)-4-(3-(trifluoromethyl)phenyl)butane-1,4-dione263

White solid (27 mg, 0.08 mmol). ¹H NMR (DMSO-d₆, 400 MHz) 6 ppm3.46-3.62 (m, 4H), 7.78 (d, J=8.53 Hz, 1H), 7.83 (t, J=7.78 Hz, 1H),7.99 (dd, J=8.53 Hz, J=1.51 Hz, 1H), 8.05 (d, J=7.78 Hz, 1H), 8.27 (s,1H), 8.35 (d, J=7.78 Hz, 1H), 8.38 (d, J=1.00 Hz, 1H), 8.79 (s, 1H);ESIMS found C₁₈H₁₃F₃N₂O₂ m/z 346.9 (M+H).

1-(1H-Benzo[d]imidazol-5-yl)-4-(2-fluorophenyl)butane-1,4-dione 265

White solid (15 mg, 0.05 mmol). ¹H NMR (DMSO-d₆, 400 MHz) 6 ppm3.33-3.43 (m, 2H), 3.47-3.52 (m, 2H), 7.30-7.39 (m, 2H), 7.62-7.73 (m,2H), 7.85 (td, J=7.72 Hz, J=1.88 Hz, 1H), 7.89 (dd, J=8.53 Hz, J=1.51Hz, 1H), 8.30 (brd, J=1.51 Hz, 1H), 8.33 (s, 1H), 12.50 (brs, 1H); ESIMSfound C₁₇H₁₃FN₂O₂ m/z 297.1 (M+H).

1-(1H-Benzo[d]imidazol-5-yl)-4-(3-methoxy phenyl)butane-1,4-dione 269

White solid (15 mg, 0.05 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.47 (s,4H), 3.84 (s, 3H), 7.12 (dd, J=2.4 Hz, J=8.4 Hz, 1H), 7.38 (t, J=8 Hz,1H), 7.49 (s, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 8.14(d, J=8.8 Hz, 1H), 8.45 (s, 1H), 9.28 (brs, 1H); ESIMS found C₁₈H₁₆N₂O₃m/z 309.0 (M+H).

1-(1H-Benzo[d]imidazol-5-yl)-4-phenylbutane-1,4-dione 274

White solid (20 mg, 0.07 mmol). ¹H NMR (DMSO-d₆, 400 MHz) 6 ppm3.40-3.46 (m, 2H), 3.47-3.55 (m, 2H), 7.53-7.60 (m, 2H), 7.62-7.71 (m,2H), 7.90 (d, J=8.78 Hz, 1H), 8.01-8.09 (m, 2H), 8.35-8.49 (m, 2H),12.80 (brs, 1H); ESIMS found C₁₇H₁₄N₂O² m/z 279.1 (M+H).

1-(1H-Indol-3-yl)-4-(2-(trifluoromethyl)phenyl)butane-1,4-dione 314

White solid (27 mg, 0.08 mmol). ¹H NMR (DMSO-d₆, 400 MHz) 6 ppm3.23-3.29 (m, 2H), 3.30-3.36 (m, 21-1), 7.13-7.25 (m, 2H), 7.48 (dd,J=7.42, 0.76 Hz, 1H), 7.73 (t, J=7.52 Hz, 1H), 7.84 (t, J=7.02 Hz, 2H),7.98 (dd, J=7.53, 1.24 Hz, 1H), 8.17 (d, J=7.26 Hz, 1H), 8.43 (s, 1H),11.97 (br. s., 1H); ESIMS found C₁₉H₁₄F₃NO₂ m/z 346.0 (M+H).

1-(1H-Indol-3-yl)-4-(4-(trifluoromethyl)phenyl)butane-1,4-dione 316

White solid (11 mg, 0.03 mmol). ¹H NMR (DMSO-d₆, 400 MHz) 6 ppm 3.18 (t,J=6.4 Hz, 2H), 3.44 (t, J=6.4 Hz, 2H), 7.11-7.27 (m, 2H), 7.49 (d, J=8Hz, 1H), 7.94 (d, J=8 Hz, 2H), 8.14 (d, J=7.6 Hz, 1H), 8.23 (d, J=8 Hz,2H), 8.43 (s, 1H), 11.97 (brs, 1H); ESIMS found C₁₉H₁₄F₃NO₂ m/z 345.9(M+H).

1-(2-Fluorophenyl)-4-(1H-indol-3-yl)butane-1,4-dione 317

White solid (10 mg, 0.03 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.33-3.42(m, 2H), 3.46-3.56 (m, 2H), 7.17 (dd, J=11.17 Hz, J=8.41 Hz, 1H), 7.214(dt, J=0.76 Hz, J=7.52 Hz, 1H), 7.26 (s, 1H), 7.26-7.34 (m, 3H),7.38-7.46 (m, 1H), 7.48-7.59 (m, H), 7.92 (td, J=7.53 Hz, J=1.76H, 1H),7.98 (d, J=3.0 Hz, 1H), 8.34-8.42 (m, 1H), 8.74 (brs, 1H); ESIMS foundC₁₈H₃₄FNO₂ m/z 296.0 (M+H).

1-(1H-Indol-3-yl)-4-(2-methoxyphenyl)butane-1,4-dione 319

White solid (60 mg, 0.20 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.33 (t,J=6.78 Hz, 2H), 3.52 (t, J=6.50 Hz, 2H), 3.93 (s, 3H), 6.94-7.06 (m,2H), 7.25-7.32 (m, 1H), 7.38-7.45 (m, 1H), 7.48 (ddd, J=8.34, 7.34, 1.88Hz, 1H), 7.79 (dd, J=7.65, 1.88 Hz, 1H), 7.96 (d, J=3.01 Hz, 1H),8.36-8.44 (m, 1H), 8.84 (brs, 1H); ESIMS found C₁₉H₃₇NO₃ m/z 308.0(M+H).

1-(1H-Indol-3-yl)-4-(3-methoxyphenyl)butane-1,4-dione 320

White solid (30 mg, 0.10 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.38 (t,J=6.8 Hz, 2H), 3.51 (t, J=6.8 Hz, 2H), 3.87 (s, 3H), 7.13 (dd, J=2.4 Hz,J=8 Hz, 1H), 7.24-7.35 (m, 2H), 7.36-7.47 (m, 2H), 7.56 (s, 1H), 7.67(d, J=8 Hz, 1H), 7.99 (s, 1H), 8.39 (dd, J=3.6 Hz, J=5.2 Hz, 1H), 8.74(brs, 1H); ESIMS found C₁₉H₁₇NO₃ m/z 308.0 (M+H).

1-(1H-Indol-3-yl)-4-phenylbutane-1,4-dione 325

White solid (16 mg, 0.06 mmol). ¹H NMR (DMSO-d₆, 400 MHz) 6 ppm3.23-3.50 (m, 4H), 7.08-7.26 (m, 2H), 7.47 (d, J=8 Hz, 1H), 7.55 (t,J=7.6 Hz, 2H), 7.66 (t, J=7.6 Hz, 1H), 8.03 (d, J=7.2 Hz, 2H), 8.14 (d,J=7.6 Hz, 1H), 8.42 (s, 1H), 11.94 (brs, 1H); ESIMS found C₁₈H₁₅NO₂ z278.0 (M+H).

1-(1H-Indazol-3-yl)-4-(2-(trifluoromethyl)phenyl)butane-1,4-dione 326

White solid (20 mg, 0.06 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.36 (t,J=6.27 Hz, 2H) 3.71 (dd, J=6.90, 5.65 Hz, 2H) 7.33 (ddd, J=8.09, 6.96,0.75 Hz, 1H) 7.45 (ddd, J=8.52 Hz, J=7.78 Hz, J=1.00 Hz, 1H) 7.53-7.62(m, 2H) 7.67 (t, J=7.64 Hz, 1H) 7.76 (dd, J=17.82, 7.53 Hz, 2H) 8.35(td, J=1.00 Hz, J=8.14 Hz, 1H), 10.57 (brs, 1H); ESIMS foundC₁₈H₁₃F₃N₂O₂ m/z 346.9 (M+H).

1-(2-Fluorophenyl)-4-(1H-indazol-3-yl)butane-1,4-dione 329

White solid (11 mg, 0.04 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.38-3.45(m, 2H), 3.47-3.63 (m, 2H), 7.28-7.50 (m, 4H), 7.65-7.73 (m, 2H), 7.86(td, J=7.65, 1.76 Hz, 1H), 8.15 (d, J=8.28 Hz, 1H); ESIMS foundC₁₇H₁₃FN₂O₂ z 297.0 (M+H).

1-(1H-Indazol-3-yl)-4-(2-methoxyphenyl)butane-1,4-dione 332

Yellow solid (30 mg, 0.10 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.51-3.59(m, 2H), 3.60-3.70 (m, 2H), 3.94 (s, 3H), 6.95-7.07 (m, 2H), 7.30 (ddd,J=8.09, 7.09, 0.88 Hz, 1H), 7.39-7.45 (m, 1H), 7.45-7.51 (m, 1H), 7.53(d, J=8.53 Hz, 1H), 7.82 (dd, J=7.65, 1.88 Hz, 1H), 8.34 (d, J=8.05 Hz,1H); ESIMS found C₁₈H₁₆N₂O₃ m/z 309.0 (M+H).

1-(1H-Indazol-3-yl)-4-(4-methoxyphenyl)butane-1,4-dione 334

White solid (50 mg, 0.16 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.50 (t,J=6.4 Hz, 2H), 3.69 (t, J=6.4 Hz, 2H), 3.89 (s, 3H), 6.97 (d, J=8.8 Hz,2H), 7.30 (t, J=7.6 Hz, 1H), 7.43 (t, J=7.6 Hz, 1H), 7.53 (d, J=8.4 Hz,1H), 8.06 (d, J=8.8 Hz, 2H), 8.32 (d, J=8 Hz, 1H); ESIMS foundC₁₈H₁₆N₂O₃ m/z 309.2 (M+H).

1-(1H-Indazol-3-yl)-4-phenylbutane-1,4-dione 338

White solid (25 mg, 0.09 mmol). ¹H NMR (DMSO-d₆, 400 MHz) 6 ppm3.44-3.50 (m, 2H), 3.50-3.58 (m, 2H), 7.31 (ddd, J=8.04 Hz, J=7.50 Hz,J=1.00 Hz, 114), 7.46 (ddd, J=8.28 Hz, J=7.64 Hz, J=1.28 Hz, 1H),7.53-7.60 (m, 2H), 7.67 (tt, J=7.28 Hz, J=1.24 Hz, 1H), 7.69 (td, J=8.28Hz, J=1.00 Hz, 1H), 8.01-807 (m, 2H), 8.15 (td, J=9.00, 1.00 Hz, 1H),13.87 (s, 1H); ESIMS found C₁₇H₁₄N₂O₂ m/z 279.1 (M+H).

1-(1H-indol-5-yl)-4-(o-tolyl)butane-1,4-dione 445

White solid (14 mg, 0.05 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 2.53 (s,3H), 3.32-3.45 (m, 2H), 3.52-3.61 (m, 2H), 6.68 (ddd, J=3.07, 2.07, 0.88Hz, 1H), 7.24-7.34 (m, 3H), 7.38 (dd, J=7.40, 1.38 Hz, 1H), 7.42 (d,J=8.53 Hz, 1H), 7.85 (dd, J=7.45, 0.60 Hz, 1H), 7.92 (dd, J=8.69, 1.52Hz, 1H), 8.42 (s, 1H), 8.53 (brs, 1H); ESIMS found C₁₉H₁₇NO₂ m/z 292.2(M+H).

1-(1H-Indol-5-yl)-4-(p-tolyl)butane-1,4-dione 447

White solid (11 mg, 0.04 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 2.43 (s,3H), 3.48 (t, J=6 Hz, 2H), 3.56 (t, J=6 Hz, 2H), 6.69 (s, 1H), 7.27 (s,1H), 7.29 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.4 Hz, 1H), 7.96 (dt, J=1.6 Hz,J=8.4 Hz, 1H), 7.97 (d, J=8.4 Hz, 2H), 8.44 (s, 1H); ESIMS foundC₁₉H₁₇NO₂ m/z 292.0 (M+H).

1-(1H-Indol-5-yl)-4-(thiophen-2-yl)butane-1,4-dione 451

Yellow solid (17 mg, 0.06 mmol). ¹H NMR (DMSO-d₆, 400 MHz) 6 ppm3.29-3.40 (m, 2H), 3.40-3.54 (m, 2H), 6.62 (d, J=2.76 Hz, 1H), 7.28 (dd,J=4.89, 3.89 Hz, 1H), 7.45-7.50 (m, 2H), 7.75 (dd, J=8.53, 1.51 Hz, 1H),8.01 (d, J=5.27 Hz, 1H), 8.06 (d, J=4.47 Hz, 1H), 8.35 (s, 1H), 11.49(brs, 1H); ESIMS found C₁₆H₁₃NO₂S m/z 284.0 (M+H).

1-(2-Fluorophenyl)-4-(1H-indazol-5-yl)butane-1,4-dione 495

Yellow solid (7 mg, 0.02 mmol). ¹H NMR (CD₃OD, 400 MHz) δ ppm 3.41-3.49(m, 2H), 3.52-3.60 (m, 2H), 7.22-7.35 (m, 2H), 7.61 (d, J=8.78 Hz, 2H),7.89 (td, J=7.65, 1.76 Hz, 1H), 8.07 (dd, J=8.78, 1.51 Hz, 1H), 8.24 (s,1H), 8.65 (s, 1H); ESIMS found C₁₇H₁₃FN₂O₂ m/z 297.0 (M+H).

1-(4-Fluorophenyl)-4-(1H-indazol-5-yl)butane-1,4-dione 497

White solid (10 mg, 0.03 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.44-3.51(m, 2H), 3.52-3.59 (m, 2H), 7.12-7.22 (m, 2H), 7.56 (d, J=9.03 Hz, 1H),8.04-8.15 (m, 3H), 8.23 (d, J=1.00 Hz, 1H), 8.53-8.59 (m, 1H), 10.28(brs, 1H); ESIMS found C₁₇H₁₃FN₂O₂ m/z 297.0 (M+H).

1-(1H-Indazol-5-yl)-4-(2-(trifluoromethyl)phenyl)butane-1,4-dione 498

White solid (21 mg, 0.06 mmol). ¹H NMR (DMSO-d₆, 400 MHz) 6 ppm3.26-3.37 (m, 2H), 3.45-3.57 (m, 2H), 7.63 (d, J=9.03 Hz, 1H), 7.74 (t,J=7.39 Hz, 1H), 7.85 (t, J=7.76 Hz, 2H), 7.98 (d, J=8.53 Hz, 2H), 8.29(s, 1H), 8.64 (s, 1H), 13.42 (brs, 1H); ESIMS found C₁₈H₁₃F₃N₂O₂ m/z347.0 (M+H).

1-(1H-Indazol-5-yl)-4-(p-tolyl)butane-1,4-dione 503

White solid (15 mg, 0.05 mmol). ¹H NMR (DMSO-d₆, 400 MHz) 6 ppm 2.40 (s,3H), 3.40 (t, J=4 Hz, 2H), 3.46 (t, J=3.6 Hz, 2H), 7.36 (d, J=8 Hz, 2H),7.63 (d, J=8.8 Hz, 1H), 7.93 (d, J=8 Hz, 2H), 7.95 (d, J=8.8 Hz, 1H),8.29 (s, 1H), 8.62 (s, 1H); ESIMS found C₁₈H₁₆N₂O₂ m/z 293.0 (M+H).

1-(1H-Indazol-5-yl)-4-(pyridin-2-yl)butane-1,4-dione 507

White solid (20 mg, 0.07 mmol). ¹H NMR (DMSO-d₆, 400 MHz) 6 ppm3.49-3.54 (m, 2H), 3.54-3.59 (m, 2H), 7.62 (d, J=8.78 Hz, 1H), 7.69(ddd, J=7.40 Hz, J=4.77 Hz, J=1.38 Hz, 1H), 7.93-7.99 (m, 2H), 8.03 (dt,J=1.76 Hz, J=7.52 Hz, 1H), 8.29 (s, 1H), 8.62 (s, 1H), 8.78 (td, J=1.00Hz, J=4.85 Hz, 1H), 13.40 (brs, 1H); ESIMS found C₁₆H₁₃N₃O₂ m/z 280.1(M+H).

1-(1H-Indazol-5-yl)-4-phenylbutane-1,4-dione 513

White solid (18 mg, 0.06 mmol). ¹H NMR (DMSO-d₆, 400 MHz) 6 ppm3.40-3.46 (m, 2H), 3.46-3.53 (m, 2H), 7.56 (t, J=7.28, 2H), 7.60-7.70(m, 2H), 7.96 (dd, J=8.78 Hz, J=1.51 Hz, 1H), 8.01-8.07 (m, 2H), 8.29(s, 1H), 8.62 (s, 1H), 13.39 (brs, 1H); ESIMS found C₁₇H₁₄N₂O₂ m/z 279.0(M+H).

1-(Furan-2-yl)-4-(1H-indazol-5-yl)butane-1,4-dione 515

White solid (12 mg, 0.05 mmol). ¹H NMR (DMSO-d₆, 400 MHz) 6 ppm 3.23(dd, J=6.78 Hz, J=5.27 Hz, 2H), 3.47 (dd, J=6.90 Hz, J=5.14 Hz, 2H),6.74 (dd, J=3.51 Hz, J=1.76 Hz, 1H), 7.51 (dd, J=3.51 Hz, J=0.75 Hz,1H), 7.62 (d, J=8.78 Hz, 1H), 7.95 (dd, J=1.76 Hz, J=8.74 Hz, 1H), 8.01(dd, J=0.76 Hz, J=1.52 Hz, 1H), 8.28 (s, 1H), 8.60 (s, 1H), 13.40 (brs,1H); ESIMS found C₁₅H₁₂N₂O₃ m/z 269.1 (M+H).

1-(1H-Indol-3-yl)-4-(o-tolyl)butane-1,4-dione 518

Yellow solid (14 mg, 0.05 mmol). ¹H NMR (DMSO-d₆, 400 MHz) 6 ppm 2.39(s, 3H), 3.22-3.33 (m, 414), 7.14-7.25 (m, 2H), 7.26-7.39 (m, 2H),7.40-7.55 (m, 2H), 7.87 (d, J=7.53 Hz, 1H), 8.15 (d, J=7.03 Hz, 1H),8.41 (s, 1H), 11.97 (brs, 1H); ESIMS found C₁₉H₁₇NO₂ m/z 292.2 (M+H).

1-(1H-Indol-3-yl)-4-(thiophen-2-yl)butane-1,4-dione 524

White solid (28 mg, 0.10 mmol). ¹H NMR (DMSO-d₆, 400 MHz) 6 ppm3.26-3.37 (m, 4H), 7.13-7.23 (m, 2H), 7.27 (dd, J=4.77 Hz, J=3.76 Hz,1H), 7.47 (d, J=7.43 Hz, 1H), 8.00 (d, J=5.02 Hz, 1H), 8.04 (dd, J=3.76Hz, J=1.00 Hz, 1H), 8.13 (d, J=7.54 Hz, 1H), 8.40 (s, 1H), 11.96 (brs,1H); ESIMS found C₁₆H₁₃NO₂S m/z 283.9 (M+H).

1-(1H-Indazol-3-yl)-4-(o-tolyl)butane-1,4-dione 528

Yellow solid (30 mg, 0.10 mmol). ¹H NMR (DMSO-d₆, 400 MHz) 6 ppm 2.38(s, 3H), 3.33-3.43 (m, 2H), 3.48-3.60 (m, 2H), 7.25-7.40 (m, 3H),7.40-7.53 (m, 2H), 7.69 (d. J=8.04 Hz, 1H), 7.88 (d, J=7.52 Hz, 1H),8.15 (d, J=7.80 Hz, 1H); ESIMS found C₁₈H₁₆N₂O₂ m/z 293 (M+H).

1-(1H-Indazol-3-yl)-4-(m-tolyl)butane-1,4-dione 529

White solid (85 mg, 0.29 mmol). ¹H NMR (DMSO-d₆, 400 MHz) 6 ppm 2.40 (s,3H), 3.42-3.49 (m, 2H), 3.50-3.56 (m, 2H), 7.31 (ddd, J=8.03 Hz, J=7.03Hz, J=1.00 Hz, 1H), 7.41-7.51 (m, 3H), 7.69 (d, J=8.53 Hz, 1H),7.80-7.86 (m, 2H), 8.15 (dt, J=8.09 Hz, J=0.97 Hz, 1H), 13.87 (brs, 1H);ESIMS found C₁₈H₁₆N₂O₂ m/z 293.1 (M+H).

Example 3

Preparation of1-(5,8-dihydroxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-phenylpropane-1,3-dione(3) and1-(5,8-dimethoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-phenylpropane-1,3-dione(6) is depicted below in Scheme 17.

Step 1

To a well stirred solution of1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(dimethylamino)propan-1-one(XXXIII) (100 mg, 0.425 mmol, 1.0 eq) in 1,4-dioxane (3 mL) was addednicotinaldehyde (LXXX) (55 mg, 0.511 mmol, 1.2 eq),3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (32 mg, 0.128mmol, 0.3 eq) and TEA (0.5 mL). The reaction mixture was refluxed for 16h. TLC analysis (PE:EtOAc 3:1) showed the reaction was complete. Thesolution was cooled to room temperature and diluted with water (20 mL).The product was extracted with EtOAc (3×30 mL). The combined organiclayers was dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by HPLC to give1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-(pyridin-3-yl)butane-1,4-dione(14) as a white solid. (13 mg, 0.04 mmol, 10.3% yield). ¹H NMR (CDCl₃,400 MHz) δ ppm 3.43 (s, 4H), 4.27-4.31 (m, 2H), 4.31-4.38 (m, 21-1),6.94 (AA′BB′quartet, 1H), 7.42-7.49 (m, 1H), 7.55-7.61 (m, 2H), 8.31 (d,J=8.4 Hz, 1H), 8.81 (brs, 1H), 9.28 (brs, 1H); ESIMS found C₁₇H₁₅NO₄ m/z298.0 (M+H).

The following compound was prepared in accordance with the proceduredescribed in the above Example 3.

1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-4-(pyridin-4-yl)butane-1,4-dione15

White solid (30 mg, 0.10 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.32-3.50(m, 4H), 4.24-4.45 (m, 4H), 6.94 (AA′BB′quartet, 1H), 7.52-7.64 (m, 2H),7.82 (d, J=6 Hz, 2H), 8.84 (d, J=5.6 Hz, 2H); ESIMS found C₁₇H₁₅NO₄ m/z298.0 (M+H).

1-(3,4-Dimethoxyphenyl)-4-(pyridin-2-yl)butane-1,4-dione 207

White solid (12 mg, 0.04 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.46 (t,J=6.4 Hz, 2H), 3.69 (t, J=6.4 Hz, 21-1), 3.93 (s, 3H), 3.97 (s, 31-1),6.93 (d, J=8.4 Hz, 1H), 7.51 (dd, J=4.8 Hz, J=7.6 Hz, 1H), 7.58 (s, 1H),7.71 (dd, J=2 Hz, J=8.4 Hz, 1H), 7.87 (t, 1H), 8.07 (d, J=7.6 Hz, 1H),8.74 (d, J=4.4 Hz, 1H); ESIMS found C₁₇H₁₇NO₄ m/z 300.0 (M+H).

1-(3,4-Dimethoxyphenyl)-4-(pyridin-3-yl)butane-1,4-dione 208

White solid (10 mg, 0.03 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.41-3.53(m, 4H), 3.94 (s, 3H), 3.97 (s, 3H), 6.94 (d, J=8.4 Hz, 1H), 7.48 (dd,J=4.8 Hz, J=7.6 Hz, 1H), 7.56 (d, J=1.6 Hz, 1H), 7.71 (dd, J=1.6 Hz, J=8Hz, 1H), 8.34 (d, J=8 Hz, 1H), 8.82 (d, J=3.2 Hz, 1H), 9.29 (s, 1H);ESIMS found C₁₇H₁₇NO₄ m/z 300.0 (M+H).

1-(3,4-Dimethoxyphenyl)-4-(pyridin-4-yl)butane-1,4-dione 209

White solid (40 mg, 0.13 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.42 (t,J=6 Hz, 2H), 3.48 (t, J=6.4 Hz, 2H), 3.94 (s, 3H), 3.97 (s, 3H), 6.93(d, J=8 Hz, 1H), 7.56 (d, J=2 Hz, 1H), 7.70 (dd, J=2 Hz, J=8.4 Hz, 1H),7.83 (dd, J=1.2 Hz, J=8.4 Hz, 2H), 8.85 (dd, J=1.6 Hz, J=6 Hz, 2H);ESIMS found C₁₇H_(H)NO₄ m/z 300.0 (M+H).

1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-4-(pyrimidin-2-yl)butane-1,4-dione339

White solid (20 mg, 0.07 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.46 (t,J=6.40 Hz, 2H), 3.65 (t, J=6.30 Hz, 2H), 4.24-4.36 (m, 4H), 6.86-6.95(m, 1H), 7.46 (t, J=4.77 Hz, 1H), 7.51-7.61 (m, 2H), 8.95 (d, J=4.90 Hz,2H); ESIMS found C₁₆H₁₄N₂O₄ m/z 299.0 (M+H).

1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-4-(pyrimidin-4-yl)butane-1,4-dione340

White solid (30 mg, 0.10 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.39-3.46(m, 2H), 3.57-3.64 (m, 2H), 4.26-4.37 (m, 4H), 6.89-6.96 (m, 1H),7.52-7.60 (m, 2H), 7.91 (dd, J=5.02 Hz, J=1.51 Hz, 1H), 8.99 (d, J=5.02Hz, 1H), 9.40 (d, J=1.26 Hz, 1H); ESIMS found C₁₆H₁₄N₂O₄ m/z 299.1(M+H).

1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-4-(pyridazin-3-yl)butane-1,4-dione341

White solid (30 mg, 0.10 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.41-3.48(m, 2H), 3.75-3.84 (m, 2H), 4.24-4.34 (m, 4H), 6.87-6.94 (m, 1H),7.50-7.58 (m, 2H), 7.64 (dd, J=8.53 Hz, J=5.02 Hz, 1H), 8.11 (dd, J=8.53Hz, J=1.76 Hz, 1H), 9.33 (dd, J=5.02 Hz, J=1.76 Hz, 1H); ESIMS foundC₁₆H₁₄N₂O₄ m/z 299.0 (M+H).

1-(Chroman-6-yl)-4-(pyrimidin-2-yl)butane-1,4-dione 362

Brown oil (175.7 mg, 0.59 mmol). ¹H NMR (DMSO-d₆, 500 MHz) 6 ppm 1.95(quin, J=5.50 Hz, 2H), 2.81 (t, J=6.31 Hz, 2H), 3.36 (t, J=5.50 Hz, 2H),3.50 (t, J=6.00 Hz, 2H), 4.22 (t, J=5.20 Hz, 2H), 6.84 (d, J=8.78 Hz,1H), 7.72-7.76 (m, 2H), 7.77 (s, 1H), 9.04 (d, J=4.94 Hz, 2H); ESIMSfound C₁₇H₁₆N₂O₃ m/z 296.9 (M+H).

1-(Benzo[d][1,3]dioxol-5-yl)-4-(pyrimidin-2-yl)butane-1,4-dione 372

Light brown solid (55.2 mg, 0.19 mmol). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm3.38 (t, J=6.10 Hz, 2H), 3.51 (t, J=6.10 Hz, 2H), 6.15 (s, 2H), 7.06 (d,J=8.23 Hz, 1H), 7.47 (d, f=−1.65 Hz, 1H), 7.68 (dd, J=8.23, 1.65 Hz,1H), 7.74 (t, J=4.81 Hz, 1H), 9.04 (d, J=4.39 Hz, 2H); ESIMS foundC₁₅H₁₂N₂O₄ m/z 385.1 (M+H).

1-(3,4-Dimethoxyphenyl)-4-(pyrimidin-5-yl)butane-1,4-dione 430

White solid (10 mg, 0.03 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.40 (t,J=5.6 Hz, 2H), 3.51 (t, J=6 Hz, 2H), 3.93 (s, 3H), 3.97 (s, 3H), 6.93(d, J=8.4 Hz, 1H), 7.53 (d, J=2 Hz, 1H), 7.69 (dd, J=2 Hz, J=8.4 Hz,1H), 9.33 (s, 2H), 9.39 (s, 1H); ESIMS found C₁₆H₁₆N₂O₄ m/z 301.0 (M+H).

1-(3,4-Dimethoxyphenyl)-4-(pyrimidin-2-yl)butane-1,4-dione 431

White solid (70 mg, 0.23 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.51 (t,J=6.4 Hz, 2H), 3.68 (t, J=6.4 Hz, 2H), 3.93 (s, 3H), 3.96 (s, 3H), 6.92(d, J=8.4 Hz, 1H), 7.48 (t, J=4.8 Hz, 1H), 7.55 (d, J=1.6 Hz, 1H), 7.70(dd, J=2 Hz, J=8.4 Hz, 1H), 8.96 (d, J=4.4 Hz, 2H); ESIMS foundC₁₆H₁₆N₂O₄ m/z 301.1 (M+H).

1-(3,4-Dimethoxyphenyl)-4-(pyrimidin-4-yl)butane-1,4-dione 432

White solid (40 mg, 0.13 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.48 (t,J=6 Hz, 2H), 3.62 (t, J=6 Hz, 2H), 3.93 (s, 3H), 3.96 (s, 3H), 6.92 (d,J=8 Hz, 1H), 7.54 (d, J=1.2 Hz, 1H), 7.68 (d, J=8 Hz, 1H), 7.92 (d,J=4.8 Hz, 1H), 9.00 (d, J=5.4 Hz, 1H), 9.41 (s, 1H); ESIMS foundC₁₆H₁₆N₂O₄ m/z 301.0 (M+H).

1-(3,4-Dimethoxyphenyl)-4-(pyridazin-3-yl)butane-1,4-dione 433

White solid (70 mg, 0.23 mmol). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.52 (t,J=6 Hz, 2H), 3.84 (t, J=6 Hz, 2H), 3.93 (s, 3H), 3.97 (s, 3H), 6.94 (d,J=8.4 Hz, 1H), 7.56 (d, J=1.6 Hz, 1H), 7.62-7.74 (m, 2H), 8.15 (dd, J=2Hz, J=8.4 Hz, 1H), 9.36 (dd, J=2 Hz, J=4.8 Hz, 1H); ESIMS foundC₁₆H₁₆N₂O₄ m/z 301.1 (M+H).

1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-4-(3-methylpyridin-2-yl)butane-1,4-dione 568

White solid (207.8 mg, 0.30 mmol, 7.9% yield). ¹H NMR (DMSO-d₆, 500 MHz)δ ppm 2.45 (s, 3H), 3.29-3.32 (m, 2H), 3.42-3.45 (m, 2H), 4.28-4.30 (m,2H), 4.32-4.34 (m, 2H), 6.98 (d, J=8.4 Hz, 1H), 7.47 (d, J=2.1 Hz, 1H),7.51-7.55 (m, 2H), 7.78 (dd, J=0.7 Hz, 7.7 Hz, 1H), 8.59 (dd, J=1.0 Hz,J=4.6 Hz, 1H); ESIMS found C₁₈H₁₇NO₄ m/z 312.0 (M+H).

1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-4-(3-fluoropyridin-2-yl)butane-1,4-dione 569

White solid (94.8 mg, 0.30 mmol, 3.8% yield). ¹H NMR (DMSO-d₆, 500 MHz)δ ppm 3.32-3.34 (m, 2H), 3.43-3.46 (m, 2H), 4.29-4.30 (m, 2H), 4.33-4.34(m, 2H), 6.99 (d, J=8.4 Hz, 1H), 7.48 (d, J=2.1 Hz, 1H), 7.54 (dd, J=2.1Hz, J=8.4 Hz, 1H), 7.76-7.78 (m, 1H), 7.88-7.92 (m, 1H), 8.59 (dt, J=1.4Hz, J=4.5 Hz, 1H); ESIMS found C₁₇H₁₄FNO₄ m/z 315.9 (M+H).

1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-4-(3-(trifluoromethyl)pyridin-2-yl)butane-1,4-dione 570

Tan solid (449 mg, 1.23 mmol, 22.0% yield). ¹H NMR (DMSO-d₆, 500 MHz) δppm 3.32-3.35 (m, 2H), 3.45-3.48 (m, 2H), 4.29-4.30 (m, 2H), 4.33-4.34(m, 2H), 6.99 (d, J=8.4 Hz, 1H), 7.48 (d, J=2.1 Hz, 1H), 7.55 (dd, J=2.1Hz, J=8.5 Hz, 1H), 7.84 (dd, J=4.9 Hz, J=7.9 Hz, 1H), 8.37 (d, J=8.0 Hz,1H), 8.96 (d, J=4.6 Hz, 1H); ESIMS found C₁₈H₁₄F₃NO₄ m/z 366.3 (M+H).

1-(2-Fluorophenyl)-4-(pyrimidin-2-yl)butane-1,4-dione 712

Off-white solid (167.2 mg, 0.65 mmol). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm3.39 (m, 2H), 3.56 (t, J=6.10 Hz, 2H), 7.34-7.41 (m, 2H), 7.66-7.71 (m,1H), 7.74 (t, J=4.94 Hz, 1H), 7.85 (td, J=7.68, 1.65 Hz, 1H), 9.04 (d,J=4.94 Hz, 2H); ESIMS found C₁₄H₁₁FN₂O₂ m/z 259.0 (M+H).

1-(Pyrimidin-2-yl)-4-(o-tolyl)butane-1,4-dione 715

Brown solid (17.9 mg, 0.07 mmol). ¹H NMR (DMSO-d₆, 500 MHz) 6 ppm 2.38(s, 3H), 3.33 (t, J=6.10 Hz, 2H), 3.54 (t, J=6.10 Hz, 2H), 7.30 (d,J=7.43 Hz, 1H), 7.35 (t, J=7.67 Hz, 1H), 7.44 (td, J=7.60, 1.10 Hz, 1H),7.74 (t, J=4.90 Hz, 1H), 7.86 (d, J=7.68 Hz, 1H), 9.04 (d, J=4.94 Hz,2H); ESIMS found C₁₅H₁₄N₂O₂ m/z 255.0 (M+H).

1-(Pyrimidin-2-yl)-4-(2-(trifluoromethyl)phenyl)butane-1,4-dione 716

Light brown solid (85.8 mg, 0.28 mmol). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm3.34 (t, J=6.30 Hz, 2H), 3.56 (t, J=6.10 Hz, 2H), 7.72-7.77 (m, 2H),7.81-7.88 (m, 21-1), 7.92 (d, J=7.14 Hz, 1H), 9.05 (d, J=4.94 Hz, 2H);ESIMS found C₁₅H₁₁F₃N₂O₂ m/z 309.0 (M+H).

1-Phenyl-4-(pyrimidin-2-yl)butane-1,4-dione 718

Off-white solid (186.5 mg, 0.78 mmol). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm3.46 (t, J=6.10 Hz, 2H), 3.56 (t, J=6.10 Hz, 2H), 7.56 (t, J=7.70 Hz,2H), 7.67 (t, J=7.40 Hz, 1H), 7.75 (t, J=4.94 Hz, 1H), 8.02 (d, J=7.36Hz, 2H), 9.05 (d, J=4.94 Hz, 2H); ESIMS found C₁₄H₁₂N₂O₂ m/z 241.1(M+H).

1-(Pyrimidin-2-yl)-4-(5,6,7,8-tetrahydronaphthalen-2-yl)butane-1,4-dione737

Off-white solid (480 mg, 1.63 mmol, 24.2% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 1.75-1.77 (m, 4H), 2.78-2.80 (m, 4H), 3.38-3.41 (m, 2H),3.51-3.53 (m, 2H), 7.21 (d, J=7.8 Hz, 1H), 7.61-7.71 (m, 2H), 7.74 (t,J=4.9 Hz, 1H), 9.04 (d, J=4.9 Hz, 1H); ESIMS found C₁₈H₁₈N₂O₂ m/z 295.0(M+H).

1-(3-Chloropyridin-2-yl)-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)butane-1,4-dione 767

White solid (311 mg, 0.94 mmol, 12.6% yield). ¹H NMR (DMSO-d₆, 500 MHz)δ ppm 3.30-3.34 (m, 2H), 3.40-3.43 (m, 2H), 4.28-4.30 (m, 2H), 4.33-4.34(m, 2H), 6.99 (d, J=8.4 Hz, 1H), 7.48 (d, J=2.1 Hz, 1H), 7.54 (dd, J=2.1Hz, J=8.4 Hz, 1H), 7.65 (dd, J=4.6 Hz, J=8.2 Hz, 1H), 8.08 (dd, J=1.3Hz, J=8.2 Hz, 1H), 8.67 (dd, J=1.3 Hz, J=4.5 Hz, 1H); ESIMS foundC₁₇H₁₄ClNO₄ m/z 331.9 (M+H).

Example 4

Preparation of1-(5,8-dihydroxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-phenylpropane-1,3-dione(3) and1-(5,8-dimethoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-phenylpropane-1,3-dione(6) is depicted below in Scheme 18.

Step 1

A solution of crude2-bromo-1-(5,8-dimethoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethanone(XVI) (1.1 g, 3.36 mmol), 1,3-diphenylpropane-1,3-dione (LXXXI) (778 mg,3.47 mmol), K₂CO₃ (480 mg, 3.47 mmol), and KI (10 mg) in acetone washeated to reflux for 2 h. The reaction mixture was cooled, filtered andconcentrated under vacuum. The residue was purified by columnchromatography on silica gel (20% EtOAc/PE) to give2-benzoyl-4-(5,8-dimethoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-phenylbutane-1,4-dione(LXXXII) (1.1 g, 2.39 mmol, 70% yield for two steps) as a yellow solid.¹H NMR (CDCl₃, 500 MHz) δ ppm 3.79-3.88 (m, 5H), 3.90 (s, 3H), 4.36 (dd,J=19.32 Hz, 4.52 Hz, 4H), 6.08 (t, J=6.40 Hz, 1H), 6.98 (s, 1H)7.43-7.52 (m, 4H), 7.54-7.63 (m, 2H), 8.02 (d, J=7.53 Hz, 4H).

Step 2

A solution of2-benzoyl-4-(5,8-dimethoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-phenylbutane-1,4-dione(LXXXII) (1.1 g, 2.4 mmol) in EtOH (20 mL) was added 2% aqueous NaOH (20mL, 10 mmol) dropwise at 10° C. and then stirred at room temperature for18 h. The reaction mixture was filtered, and the solid was washed withwater (20 mL), 10% EtOAc/PE (50 mL) and dissolved in DCM (60 mL). TheDCM layer was washed with 0.5 N HCl (20 mL), brine (20 mL), dried overanhydrous Na₂SO₄ and concentrated under vacuum to produce1-(5,8-dimethoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-phenylpropane-1,3-dione(6) (750 mg, 2.19 mmol, 88% yield) as a yellow solid. ¹H NMR (CDCl₃, 500MHz) δ ppm 3.42 (d, J=6.02 Hz, 2H), 3.49 (d, J=6.02 Hz, 2H), 3.87 (s,3H), 3.96 (s, 3H), 4.37 (dd, J=14.18 Hz, 4.89 Hz, 4H), 6.97 (s, 1H),7.42-7.52 (m, 2H), 7.56 (d, J=7.28 Hz, 1H), 8.04 (d, J=7.28 Hz, 2H).

Step 3

To a solution of1-(5,8-dimethoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-phenylpropane-1,3-dione(6) (750 mg, 2.1 mmol) in anhydrous DCM (100 mL) was added a solution ofBBr₃ (0.56 mL, 6.3 mmol) in anhydrous DCM (1 mL) at −10° C. dropwise.This reaction solution was stirred at −10° C. for 3 h and then quenchedwith ice water (40 mL). The DCM layer was dried over anhydrous Na₂SO₄,and concentrated under vacuum. The residue was purified by the silicagel column (10% MeOH/DCM), and recrystallized with(MeOH:DCM:EtOAc=1:2:2) (20 mL) to yield1-(5,8-dihydroxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-phenylpropane-1,3-dione(3) as a light yellow solid (200 mg, 0.64 mmol, 29.0% yield). ¹H NMR(DMSO-d₆, 500 MHz) δ ppm 3.23-3.49 (m, 4H), 4.26 (d, J=4 Hz, 2H), 4.33(d, J=2.4 Hz, 2H), 6.96 (s, 1H), 7.55 (t, J=7.2 Hz, 2H), 7.66 (t, J=7.2Hz, 1H), 8.01 (d, J=7.6 Hz, 2H), 9.06 (s, 1H), 11.81 (s, 1H); ESIMSfound C₁₇H₁₄O₆ m/z 315.1 (M+H).

The following compound was prepared in accordance with the proceduredescribed in the above Example 4.

1-(7,8-dihydroxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-phenylbutane-1,4-dione4

Light yellow solid (160 mg, 0.51 mmol, 69.7% yield). ¹H NMR (CDCl₃, 500MHz): δ ppm 3.37-3.45 (m, 4H), 4.27 (t, J=4 Hz, 2H), 4.41 (t, J=4 Hz,2H), 5.49 (s, 1H), 7.03 (s, 1H), 7.49 (t, J=7.6 Hz, 2H), 7.59 (t, J=7.6Hz, 1H), 8.03 (d, J=7.6 Hz, 1H), 12.08 (s, 1H); ESIMS found C₁₈H₁₆O₆ m/z329.1 (M+H).

Evaluation of Biological Activity

The biological activity of the compounds described herein can be testedusing any suitable assay known to those of skill in the art, e.g., thoseassays described in WO 2001/053268 or WO 2005/009997, both of which areincorporated by reference in their entireties. For example, the activityof a compound may be tested using one or more of the test methodsdescribed below.

Example 5

Compounds that enhance the Wnt activity, or Activators, were assayed asfollows. Reporter cell lines were generated by stably transducing cellsof colon cancer cell lines (with a lentiviral construct that included aWnt-responsive promoter driving expression of the firefly luciferasegene).

Lentiviral constructs were made in which the SP5 promoter, a promoterhaving eight TCF/LEF binding sites derived from the SP5 promoter, waslinked upstream of the firefly luciferase gene. The lentiviralconstructs also included a hygromycin resistance gene as a selectablemarker. The SP5 promoter construct was used to transduce SW480 cells, acolon cancer cell line having a mutated APC gene that generates atruncated APC protein, leading to de-regulated accumulation ofβ-catenin.

Cultured SW480 cells bearing a reporter construct were distributed atapproximately 10,000 cells per well into 384- or 96-well multiwellplates. Compounds from a small molecule compound library were then addedto the wells in half-log dilutions using a maximum concentration ofthree or ten micromolar. A series of control wells for each cell typereceived only buffer and compound solvent DMSO. Twenty-four hours afterthe addition of compound, reporter activity for luciferase was assayed,for example, by addition of the BrightGlo luminescence reagent (Promega)and the Victor3 plate reader (Perkin Elmer). Readings were normalized toDMSO only treated cells, and any activities above DMSO were consideredactivation. Compounds were considered activators if reporter activitieswere 2× fold or greater than DMSO. EC₅₀ is the concentration at halfmaximal activation. Table 2 shows the activity of selected activators.

TABLE 2 Wnt activation, Compound EC₅₀ (μM) 1 0.005 2 0.001-0.003 3 >104 >10 9 0.1 10 >10 11 0.013 12 0.005 13 0.192 14 0.306 15 0.09 16 0.00718 >10 19 0.003 21 0.031 28 0.009 61 0.025 68 0.006 69 >10 71 0.002576 >10 80 0.01 207 >10 208 >10 209 >10 210 0.002 213 0.018 214 0.01 2160.011 217 0.343 222 0.003 232 0.134 235 0.494 238 >10 240 0.669 2420.789 248 >10 249 0.004 252 0.001 255 0.017 258 0.016 261 0.042 263 >10265 0.201 269 >10 274 6.8 275 0.009 278 0.018 281 0.061 287 0.087288 >10 291 0.125 292 0.595 294 1.721 300 0.018 301 0.039 307 0.055 3100.068 313 0.044 314 0.016 316 >10 317 >10 319 0.279 320 >10 325 0.063326 0.117 329 0.089 332 0.680 334 >10 338 0.064 339 0.009 340 0.209 3410.095 342 0.009 343 0.351 344 0.307 345 >10 346 0.024 358 0.014 3620.188 364 0.013 365 0.033 368 0.016 372 0.097 374 0.013 375 0.071379 >10 385 0.165 425 5.95 426 8.80 430 >10 431 >10 432 4.8 433 >10 4422.15 445 0.010 447 >10 451 0.037 455 0.032 456 0.673 457 2.89 462 0.424485 >10 495 0.008 497 0.048 498 0.012 503 0.487 507 0.036 513 0.039 5150.127 518 0.646 524 0.088 528 0.148 529 0.695 538 0.063 541 2.81 544 0.9547 >10 554 >10 557 0.026 559 0.340 560 0.055 562 0.106 569 0.00196 5700.026 718 0.681 737 0.022 767 0.002164

The term “comprising” as used herein is synonymous with “including,”“containing,” or “characterized by,” and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps.

What is claimed is:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 7-12membered heteroaryl, wherein a carbon atom on the ring is attached tothe carbonyl carbon; Ring B is selected from the group consisting ofphenyl and a 5-6 membered heteroaryl, wherein a carbon atom on the ringis attached to the carbonyl carbon; R¹ is a substituent attached to RingA and is independently selected at each occurrence from the groupconsisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide,—OR³, CF₃, and CN; R² is a substituent attached to Ring B and isindependently selected at each occurrence from the group consisting ofH, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl,halide, —OR³, CF₃, and CN; each R³ is independently selected from thegroup consisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, andCF₃; each R^(3b) is independently selected from the group consisting ofH and unsubstituted —C₁₋₃ alkyl; each n is an integer of 1 to 10; andeach m is an integer of 1 to 5; with the proviso that the compound ofFormula I is not a compound selected from the group consisting of:


2. The compound of claim 1, wherein the compound of Formula I isselected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 3. A compound of FormulaIa:

or a pharmaceutically acceptable salt thereof, wherein: Ring A is

Ring B is selected from the group consisting of

each R¹ is a substituent attached to Ring A and is independentlyselected at each occurrence from the group consisting of H,unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, halide, —OR³, CF₃, and CN;R^(2a) is selected from the group consisting of unsubstituted —C₁₋₆alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl, Cl, Br, I, —OR^(3a),CF₃, and CN; R^(2b) is selected from the group consisting ofunsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl,halide, —OR^(3a), CF₃, and CN; R^(2c) is 2-5 substituents, eachindependently selected at each occurrence from the group consisting ofunsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl,halide, —OR³, CF₃, and CN; R^(2d) is 1-4 substituents, eachindependently selected at each occurrence from the group consisting ofunsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl,halide, —OR³, CF₃, and CN; R^(2e) is 1-4 substituents, eachindependently selected at each occurrence from the group consisting ofH, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl,halide, —OR³, CF₃, and CN; R^(2f) is 1-3 substituents, eachindependently selected at each occurrence from the group consisting ofunsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl,halide, —OR³, CF₃, and CN; R^(2g) is 1-3 substituents, eachindependently selected at each occurrence from the group consisting ofH, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl,halide, —OR³, CF₃, and CN; each R³ is independently selected from thegroup consisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, andCF₃; each R^(3a) is independently selected from the group consisting ofunsubstituted —C₂₋₆ alkyl, —C₁₋₃ haloalkyl, and CF₃; each R^(3b) isindependently selected from the group consisting of H and unsubstituted—C₁₋₃ alkyl; each W is N or C, wherein at least two W are N; each U is Nor C, wherein at least one U is N and at least one U is C; G is NH or O;each J is N or C, wherein at least one J is C; and n is an integer of 1to
 7. 4. The compound of claim 3, wherein the compound of Formula Ia isselected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 5. A compound of FormulaIc:

or a pharmaceutically acceptable salt thereof, wherein: Ring A is

Ring B is selected from the group consisting of phenyl and a 5-6membered heteroaryl, wherein a carbon atom on the ring is attached tothe carbonyl carbon; each R¹ is independently selected at eachoccurrence from the group consisting of H, unsubstituted —C₁₋₆ alkyl,—C₁₋₃ haloalkyl, halide, —OR³, CF₃, and CN; each R² is independentlyselected at each occurrence from the group consisting of H,unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(3b))₂, —C₁₋₃ haloalkyl,halide, —OR³, CF₃, and CN; each R³ is independently selected from thegroup consisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, andCF₃; each R^(3b) is independently selected from the group consisting ofH and unsubstituted —C₁₋₃ alkyl; each M is independently selected fromthe group consisting of N, C, S and O, wherein if one M is C, the otherM is selected from the group consisting of N, S, and O; m is an integerof 1 to 5; and n is an integer of 1 to
 10. 6. The compound of claim 5,wherein the compound of Formula Ic is selected from the group consistingof:

or a pharmaceutically acceptable salt thereof.
 7. A compound of FormulaII:

or a pharmaceutically acceptable salt thereof, wherein: Ring C is a 5-6membered heteroaryl, wherein a carbon atom on the ring is attached tothe carbonyl carbon; Ring D is selected from the group consisting ofphenyl and a 5-6 membered heteroaryl, wherein a carbon atom on the ringis attached to the carbonyl carbon; each R⁴ is independently selected ateach occurrence from the group consisting of H, unsubstituted —C₁₋₆alkyl, —C₁₋₃ haloalkyl, halide, —OR⁶, CF₃, and CN; each R⁵ isindependently selected at each occurrence from the group consisting ofH, unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(6b))₂, —C₁₋₃ haloalkyl,halide, —OR⁶, CF₃, and CN; each R⁶ is independently selected from thegroup consisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, andCF₃; each R^(6b) is independently selected from the group consisting ofH and unsubstituted —C₁₋₃ alkyl; p is an integer of 1 to 4; and q is aninteger of 1 to
 5. with the proviso that the compound of Formula II isnot a compound selected from the group consisting of:


8. The compound of claim 7, wherein the compound of Formula II isselected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 9. A compound of FormulaIIIa:

or a pharmaceutically acceptable salt thereof, wherein: R¹⁰ is selectedfrom the group consisting of H, unsubstituted —C₁₋₆ alkyl, —C₁₋₃haloalkyl, halide, —OR¹³, CF₃, and CN; R¹¹ is selected from the groupconsisting of unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(13b))₂, —C₁₋₃haloalkyl, halide, —OR¹³, CF₃, and CN; each R¹² is independentlyselected at each occurrence from the group consisting of H,unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(13b))₂, —C₁₋₃ haloalkyl,halide, —OR¹³, CF₃, and CN; each R¹³ is independently selected from thegroup consisting of unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, and CF₃;each R^(13b) is independently selected from the group consisting of Hand unsubstituted —C₁₋₃ alkyl; and q is an integer of 1 to 5; with theproviso that the compound of Formula IIIa is not a compound selectedfrom the group consisting of:


10. The compound of claim 9, wherein the compound of Formula IIIa isselected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 11. A compound, ofFormula IIIb:

or a pharmaceutically acceptable salt thereof, wherein: R¹⁴ is selectedfrom the group consisting of unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl,and CF₃; R¹⁵ is selected from the group consisting of unsubstituted—C₁₋₆ alkyl, —C₁₋₃ haloalkyl, and CF₃; each R¹⁶ is independentlyselected at each occurrence from the group consisting of H,unsubstituted —C₁₋₆ alkyl, —CH₂OH, —CH₂N(R^(17b))₂, —C₁₋₃ haloalkyl,halide, —OR¹⁷, CF₃, and CN; each R¹⁷ is independently selected from thegroup consisting of unsubstituted —C₁₋₆ alkyl, —C₁₋₃ haloalkyl, and CF₃;each R^(17b) is independently selected from the group consisting of Hand unsubstituted —C₁₋₃ alkyl; and q is an integer of 1 to 5; with theproviso that the compound of Formula IIIb is not a compound selectedfrom the group consisting of:


12. The compound of claim 11, wherein the compound of Formula IIIb isselected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 13. A compound, ofFormula IV:

or a pharmaceutically acceptable salt thereof, wherein: Ring F is

Ring G is selected from the group consisting of

and a 5-6 membered heteroarylR^(19d), wherein a carbon atom on the ringis attached to the carbonyl carbon; each R¹⁸ is independently selectedat each occurrence from the group consisting of H, —C₁₋₃ haloalkyl,halide, —OR²⁰, CF₃, and CN; R^(19a) is selected from the groupconsisting of H, unsubstituted —C₂₋₆ alkyl, —CH₂OH, —CH₂N(R²¹)₂, —C₁₋₃haloalkyl, F, Br, I, —OR²⁰, CF₃, and CN; each R^(19b) is independentlyselected at each occurrence from the group consisting of H,unsubstituted —C₂₋₆ alkyl, —CH₂OH, —CH₂N(R²¹)₂, —C₁₋₃ haloalkyl, halide,—OR²⁰, CF₃, and CN; R^(19c) is 2-5 substituents, each independentlyselected at each occurrence from the group consisting of H, —CH₂OH,—CH₂N(R²¹)₂, —C₁₋₃ haloalkyl, halide, —OR²⁰, CF₃, and CN; R^(19d) is 1-4substituents, each independently selected at each occurrence from thegroup consisting of H, —CH₂OH, —CH₂N(R²¹)₂, —C₁₋₃ haloalkyl, halide,—OR²⁰, CF₃, and CN; each R²⁰ is independently selected from the groupconsisting of H, unsubstituted C₃₋₆ alkyl, —C₁₋₃ haloalkyl, and CF₃;each R²¹ is independently selected from the group consisting of H andunsubstituted —C₁₋₃ alkyl; p is an integer of 1 to 13; and r is aninteger of 1 to
 5. 14. The compound of claim 13, wherein the compound ofFormula IV is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 15. A compound selectedfrom the group consisting of:

or a pharmaceutically acceptable salt thereof.
 16. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to any one of claims 1, 3, 5, 7, 9, 11, 13, and 15, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 17. A method of treating a disorder or diseaseselected from the group consisting of a neurodegenerative disease, eyedisease, osteoporosis, osteoarthropathy, osteogenesis imperfecta, bonedefects, bone fractures, periodontal disease, otosclerosis, woundhealing, oral mucositis, gastrointestinal mucositis, craniofacialdefects, and oncolytic bone disease, the method comprising administeringto the patient a therapeutically effective amount of a compoundaccording to any one of claims 1, 3, 5, 7, 9, 11, 13, and 15, or apharmaceutically acceptable salt thereof.
 18. A method of treating adisorder or disorder or disease related to differentiation and growth ofstem cells and is selected from the group consisting of hair loss,hematopoiesis related diseases, tissue regeneration related diseases,and other diseases associated with abnormalities in development, stemcell differentiation, and cell proliferation, the method comprisingadministering to the patient a therapeutically effective amount of acompound according to any one of claims 1, 3, 5, 7, 9, 11, 13, and 15,or a pharmaceutically acceptable salt thereof.
 19. A compound-elutingcoating or a controlled release system comprising a compound accordingto any one of claims 1, 3, 5, 7, 9, 11, 13, and 15, or apharmaceutically acceptable salt thereof.
 20. A medical devicecomprising a compound according to any one of claims 1, 3, 5, 7, 9, 11,13, and 15, or a pharmaceutically acceptable salt thereof.
 21. Animplant, sponge, polymer, ointment, cream or gel composition suitablefor in vivo use comprising a compound according to any one of claims 1,3, 5, 7, 9, 11, 13, and 15, or a pharmaceutically acceptable saltthereof.